DESC:FIELD OF THE INVENTION
The present invention relates to a controlled release pharmaceutical composition comprising apremilast or pharmaceutically acceptable salt thereof. Particularly the present invention relates to a controlled release oral composition comprising apremilast or salt thereof, a compressibility agent and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis; wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose; wherein the drug is administered once daily.

BACKGROUND OF THE INVENTION
Psoriasis is a long-lasting autoimmune disease characterized by patches of abnormal skin. These skin patches are typically red, itchy, and scaly. It is a chronic skin condition that produces plaques of thickened, scaling skin. There are several types of psoriasis: plaque, guttate, inverse, pustular, and erythrodermic. Plaque psoriasis, also known as psoriasis vulgaris, makes up about 90 percent of cases. Psoriasis is commonly associated with inflamed joints in about one-third of those affected.
The joint disease associated with psoriasis is referred to as psoriatic arthritis. Patients may have inflammation of any joints (arthritis), although the joints of the hands, knees, and ankles tend to be most commonly affected. Psoriatic arthritis is an inflammatory, destructive form of arthritis and needs to be treated with medications in order to stop the disease progression. Psoriasis is associated with an increased risk of psoriatic arthritis, lymphomas, cardiovascular disease, Crohn's disease and depression. Psoriatic arthritis affects up to 30 percent of individuals with psoriasis.
There is no permanent cure for psoriasis; however, various treatments can help control the symptoms. These treatments include steroid creams, vitamin D3 cream, ultraviolet light and immune system suppressing medications, such as methotrexate. Topical corticosteroid preparations are the most effective agents. Severe form of psoriasis may be treated with systemic therapies including medications by mouth or injectable treatments.
Phosphodiesterase PDE4 inhibitors are novel anti-inflammatory drugs that have recently been shown to document clinical efficacy in such auto-immune inflammatory diseases. Phosphodiesterases are ubiquitous enzymes which hydrolyse the cyclic nucleotides; cyclic adenosine-3,5- monophosphate (cAMP) and cyclic guanosine -3,5- monophosphate (cGMP), to their inactive 5'nucleotide monophosphate, 5' AMP and 5' GMP respectively. PDE4 is a cAMP specific phosphodiesterase which is located predominantly to inflammatory cells. cAMP and TNF-a play role in many diseases such as allergic and inflammatory. TNF- a is a cytokine that is released primarily by mononuclear phagocytes in response to immune stimulators. Enhanced or unregulated TNF- a production has been implicated in viral, genetic, inflammatory, allergic and autoimmune disease including but not limited to asthma, chronic obstructive pulmonary disease, osteoarthritis, rheumatoid arthritis, dermatitits, cystic fibrosis, psoriasis and psoritic arthirits etc.
Apremilast also known as ((S)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl}acetamide), has a molecular weight of 460.5. Apremilast binds to the catalytic site of the PDE4 enzyme, thereby blocking cAMP degradation. It inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. It has following formula:

salts, enantiomers, polymorphs of compounds of above formula are useful as the active ingredient in the pharmaceutical presentation of the invention. Apremilast may be described in US6020358, US7427638 and US7893101 herein incorporated by reference. Apremilast or salts thereof may be used in combination with another anti-inflammatory agent which may be administered orally in the same dosage form in accordance with the invention.
US9018243 relates to method of treating psoriasis and psoriatic arthritis using apremilast.
US6962940 relates to method of treating diseases ameliorated by the inhibition of PDE4 using apremilast.
US9468605 claims immediate release oral dosage form of apremilast.
US20140018404A1 relates to a controlled release dosage form of poorly soluble drug with swelling exipient.
There still exists a need for stable controlled release formulation of apremilast for treatment of psoriasis and psoriatic arthritis.

SUMMARY OF THE INVENTION
The present invention relates to an oral pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients in controlled release dosage form administered in patients in need thereof, for the treatment of psoriasis and atopic dermatitis.
In another embodiment, the present invention relates to the use of a controlled release oral composition comprising apremilast or salt thereof, a compressibility agent, a polymer, a swelling agent, a floating agent, and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis; wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose.
In an embodiment, the controlled release formulation comprising apremilast or pharmaceutically acceptable salts, solvate, ester thereof is administered to patients in need thereof, in daily dose of 10mg to 100mg in initial and maintenance dose period.
Further in an embodiment, the said formulation is administered once daily for the treatment of psoriasis, psoriatic arthritis and atopic dermatitis.
The formulation according to current invention comprises apremilast or a pharmaceutically acceptable salts thereof in 60mg or 75mg strength.
In an embodiment, the controlled release dosage form is prepared in accordance to the technology selected from the group consisting of use of a compressibility agent, a polymer, a swelling agent, a floating agent, and a pharmacutically acceptable excipient.
In an embodiment, the composition comprises a compressibility agent, wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose.
In an embodiment, the apremilast or salt thereof and the hydroxypropylcellulose is present in a weight ratio ranging from 1:0.1 to 1:5. Preferably, the apremilast or salt thereof and the hydroxypropylcellulose is present in a weight ratio 1:0.2 or 1: 0.56 or 1: 0.69.
In an embodiment, the apremilast or salt thereof and the hydroxypropylmethyl cellulose is present in a weight ratio ranging from 1:1 to 1:10. Preferably, the apremilast or salt thereof and the hydroxypropylmethyl cellulose is present in a weight ratio 1:3.33 or 1:2.66.
Further in an embodiment, the present invention may comprise gastric retentive composition.
In some embodiment, the controlled release dosage form provided herein comprises cationic and anionic polymer matrix with or without floating agent.
In an embodiment, the present invention relates to a stable oral pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salts and compressibility agent in controlled release manner for the treatment of psoriasis, psoriatic arthritis and atopic dermatitis.
Further, according to present invention the formulation is stable at 250C ± 20C & 60% RH ± 5 % RH
According to present invention the formulation is stable at 300C ± 20C & 75% RH ± 5 % RH
According to present invention the formulation is stable at 400C ± 20C & 75% RH ± 5 % RH
In an embodiment, the present invention relates to controlled release tablet comprising apremilast in an amount 60mg or 75mg administered once daily, a compressibility agent and a pharmacutically acceptable excipient for the treatment of psoriasis or psoriatic arthritis or atopic dermatitis.
In another embodiment, present invention relates to a controlled release tablet comprising apremilast in an amount 60mg or 75mg administered once daily as a maintenance dose after the initial titration dose is complete, a compressibility agent and a pharmacutically acceptable excipient for the treatment of psoriasis, psoriatic arthritis and atopic dermatitis.
The present invention relates to controlled release formulation comprising apremilast wherein at least 70% of drug is released in 12hrs time.
Also the invention related to a process of preparing a controlled release oral composition comprising apremilast or salt thereof, a compressibility agent, a polymer, a swelling agent, a floating agent, and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis; wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose; wherein said process comprises steps of: (a) mixing and sifting apremilast or salt thereof, the compressibility agent, the polymer, the swelling agent, floating agent and the pharmacutically acceptable excipient to obtain a blend mix; (b) roller compacting above blend to obtain a ribbon which passed through mill to obtain granules; and (c) compressing the granules of step 2 along with other the pharmacutically acceptable excipients to obtain the controlled release oral composition; wherein said process produces a compact uniform ribbon of a blend during roller compaction resulting in imporoved compressibility and content uniformity.
According to embodiments of the present invention, the pharmaceutical formulations disclosed herein can be administered to mammalian subjects, preferably humans, for the treatment of psoriasis, psoriatic arthirtis and atopic dermatitis.

DETAILED DESCRIPTION OF THE INVENTION
The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.
The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" with regard to a certain therapeutically effective pharmaceutical dose indicates that values slightly outside the cited values, e.g., plus or minus 0.1% to 10%, which are also effective and safe.
The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating metabolic disorders, produces an intended therapeutic benefit in a subject.
The term “active ingredient” (used interchangeably with “active” or “active substance” or “drug”) as used herein includes apremilast or pharmaceutically acceptable salts thereof.
The term apremilast refers to apremilast, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof all of which are collectively referred to as apremilast.
The term “treating” or “treatment” as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by apremilast in a mammal.
The term "patient" includes mammals like human and other animals. Preferably, the patient is a human.
By “pharmaceutically acceptable excipients”, it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The term ‘controlled release’ is defined as any composition or dosage form which comprises an active drug and which is formulated to provide a longer duration of pharmacological response after administration of the dosage form than is ordinarily experienced after administration of a corresponding immediate release composition comprising the same drug in the same amount. Controlled release compositions include, inter alia, those compositions described elsewhere as "extended release", "delayed release", "sustained release", "prolonged release", " compositions or dosage forms.
A “compressibility agent” refers to an agent which produces uniform and compact ribbons during roller compaction.
A "floating agent" refers to an excipient which facilitates the formulation's ability to float as a result of gas formation. Combination of foating agent and acidic ingredient provides effervescence which gives floating action.
Psoriasis is a long-lasting autoimmune disease characterized by patches of abnormal skin. These skin patches are typically red, itchy, and scaly. It is a chronic skin condition that produces plaques of thickened, scaling skin. Psoriasis is commonly associated with inflamed joints in about one-third of those affected. The joint disease associated with psoriasis is referred to as psoriatic arthritis. Patients may have inflammation of any joints (arthritis), although the joints of the hands, knees, and ankles tend to be most commonly affected. Apremilast binds to the catalytic site of the PDE4 enzyme, thereby blocking cAMP degradation. It inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells by which the drug is effective in autoimmune diseases including but not limited to psoriasis, psoriatic arthritis and atopic dermatitis.
The present invention relates to a controlled release oral composition comprising apremilast or salt thereof, a compressibility agent, and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis.
The present invention relates to a controlled release oral composition comprising apremilast or salt thereof, a compressibility agent, a polymer, a swelling agent, a floating agent, and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis; wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose.
The present invention relates to controlled release dosage form wherein the release of the drug is controlled over the period 12hrs to 24hrs to provide an extended release of apremilast at a desired absorption site and thus allow maintenance of plasma concentrations at a therapeutic level for a prolonged period of time, which can minimize potentially undesirable dose related side effects and also can reduce the frequency of administration.
In an embodiment, the present invention relates to a stable oral pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salts in controlled release manner, a compressibility agent, and a pharmacutically acceptable excipient for the treatment of psoriasis, psoriatic arthritis and atopic dermatitis.
As per the present invention, controlled release tablets prepared as mentioned in the examples of this description is stable at 250C ± 20C & 60% RH ± 5 % RH, at 300C ± 20C & 75% RH ± 5 % RH and also at 400C ± 20C & 75% RH ± 5 % RH
In another embodiment, the present invention relates to the use of an oral controlled release pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salts, thereof administered in patients in need thereof, a compressibility agent, and a pharmacutically acceptable excipient for the treatment of psoriasis, psoriatic arthritis and atopic dermatitis.
Further in an embodiment, the present invention relates to method of treating psoriasis or psoriatic arthritis or atopic dermatitis using an oral controlled release pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salts, a compressibility agent, and a pharmacutically acceptable excipient.
In an embodiment, the controlled release formulation comprising apremilast or pharmaceutically acceptable salts, solvate, ester thereof is administered to patients in need thereof, in daily dose of 10mg to 100mg in initial and maintenance dose period.
Preferably apremilast is present in an amount about 10mg to 100mg, more preferably 30mg to 80mg. Preferably 60mg or 75mg of apremilast or pharmaceutically acceptable salts thereof. The dose can be administered once or twice daily in single or divided doses. Prefered dosing regimen is once daily.The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
In another embodiment, the said formulation is administered once daily for psoriasis, psoriatic arthritis and atopic dermatitis.
Preferably the controlled release tablet comprising apremilast is administered once daily in the dose of 40mg to 100mg, more preferably in 60mg to 75mg strength.
In the pharmaceutical science, release rate of the drug can be controlled with various technologies. In an aspect, the present disclosure provides a microsphere formulation for sustained release of apremilast. The sustained release microsphere formulation can include (a) an apremilast core prepared by extrusion spheronization; and (b) a coating surrounding the apremilast core, the coating being a functional coating or a seal coating followed by a functional coating. The microsphere formulation is suitable for once-daily administration for effective management of psoriasis, psoriatic arthritis and atopic dermatitis.
In another aspect, the present disclosure provides a multiparticulate formulation for controlled release of apremilast which ensures a controlled release of drug at a desired absorption site after oral administration. The controlled release multiparticulate formulation disclosed herein can include an apremilast core, at least one or two layers of seal coating or functional coating.
In an embodiment, the controlled release dosage form is prepared in accordance to the technology selected from the group consisting of use of floating agent or use of swelling agent or use of gelling agent or matrix tablet comprising a rate limiting polymer.
In an embodiment, the controlled release dosage form is prepared with use of floating technology. Floating tablets have bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. In some embodiments, the controlled release oral dosage form further comprises a water absorbing agent.
Some non-limiting examples of floating agents include sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, magnesium bicarbonate, calcium bicarbonate and calcium carbonate.
Non-limiting examples of water absorbing agents include humectants such as sorbitol, mannitol, xylitol, maltitol, polymeric polyols, calcium chloride, sodium chloride, carrageenan (Gelcarin.RTM.), polyacrylic acid and hydrogel.
In an embodiment, the controlled release dosage form is prepared with use of swelling agent. Polymers which swell in an aqueous medium have often been used for the preparation of controlled-release dosage forms. Swellable polymers that are water-insoluble are commonly called hydrogels and water-soluble types are called hydrophilic polymers. In these swelling controlled-release systems, the release of a solute (e.g., drug, dye, etc.) is controlled by the transport of the solvent into the polymer matrix, swelling of the associated polymer, diffusion of the solute through the swollen polymer, erosion of the swollen polymer, etc.
Non limiting examples of polymers which are commonly used for controlling the release by swelling are poly(hydroxyalkyl-methacrylate), poly(vinyl alcohol), ethylene vinyl alcohol, and their copolymers, poly(ethylene oxide), and cellulose ethers such as methylcellulose (MC), and sodium carboxymethylcellulose (Na CMC).
The compressibilty agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose.
In an embodiment, the apremilast or salt thereof and the hydroxypropylcellulose is present in a weight ratio ranging from 1:0.1 to 1:5. Preferably, the apremilast or salt thereof and the hydroxypropylcellulose is present in a weight ratio 1:0.2 or 1: 0.56 or 1: 0.69.
In an embodiment, the apremilast or salt thereof and the hydroxypropylmethyl cellulose is present in a weight ratio ranging from 1:1 to 1:10. Preferably, the apremilast or salt thereof and the hydroxypropylmethyl cellulose is present in a weight ratio 1:3.33 or 1:2.66.
In an embodiment, the present invention provides matrix tablet comprising rate limiting polymer. Polymer matrices have also been used to achieve controlled release of the drug over a prolonged period of time. Such sustained or controlled release is achieved either by limiting the rate by which the surrounding gastric fluid can diffuse through the matrix and reach the drug, dissolve the drug and diffuse out again with the dissolved drug, or by using a matrix that slowly erodes, continuously exposing fresh drug to the surrounding fluid.
Further in an embodiment, the present invention may comprise gastric retentive composition. Gastro retentive dosage forms are designed to be retained in gastric region for prolonged time and enable sustained or controlled release of drug in upper part of GI ensuring optimum bioavailability.
In some embodiment, the controlled release dosage form provided herein comprises cationic and anionic polymer matrix with or without floating agent.
In an embodiment, the present invention relates to controlled release tablet comprising apremilast in an amount 60mg or 75mg administered once daily for the treatment of psoriasis or psoriatic arthritis or atopic dermatitis.
In another embodiment, present invention relates to controlled release tablet comprising apremilast in an amount 60mg or 75mg administered once daily as a maintenance dose after the initial titration dose is complete, for the treatment of psoriasis, psoriatic arthritis and atopic dermatitis.
Initial titration dose of apremilast as per approved product Otezla® starts from 10mg daily dose which is increased gradually to 60mg daily dose. Once the initial titration dose is complete, maintenance dose is continued for the further treatment. The controlled release tablet of either 60mg or 75mg can be used as a maintenance dose therapy.
The present invention relates to controlled release formulation comprising apremilast wherein at least 70% of drug is released 12hrs time.
According to embodiments of the present invention, the pharmaceutical formulations disclosed herein can be administered to mammalian subjects, preferably humans, for the treatment of psoriasis, psoriatic arthirtis and atopic dermatitis.
The tablet comprising apremilast can be administered as per the disease severity and medical requirement.
Controlled release tablets may further comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to one or more of diluents, disintegrant, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, swelling agents, basifying agents, opacifiers, colorants, gelling agents / viscosity modifying agents, antioxidants, solvents, co-solvents, and combinations thereof.
The excipients can be added intra granularly or extra granularly during tablet manufacturing.
Non-limiting examples of diluents include one or more of microcrystalline cellulose, silicified microcrystalline cellulose (e.g., Prosolv®), microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, sugars such as dextrose, mannitol, sorbitol, or sucrose and combinations thereof. The diluents according to current invention are present in an amount 5-30% w/w.
Non limiting examples of disintegrants suitable for use herein include, crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Several specific types of disintegrant are suitable for use in the formulations described herein. For example, any grade of crospovidone can be used, including for example crospovidone XL-10, and includes members selected from the group consisting of Kollidon CL.RTM., Polyplasdone XL.RTM., Kollidon CL-M.RTM., Polyplasdone XL-10.RTM., and Polyplasdone INF-10.RTM. In one embodiment, the disintegrant, if present, of the stock granulation is sodium starch glycolate, croscarmellose sodium and/or crospovidone. These materials are also referred to as insoluble polyvidone, insoluble PVP, crosslinked PVP, and PVPP. The crospovidone can be substituted with croscarmellose sodium, sodium starch glycolate. The disintegrant according to current invention are present in an amount 1-30% w/w.
Non-limiting examples of glidants and lubricants include one or more of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate. The glidant according to current invention are present in an amount 0.1-5% w/w.
Non limiting examples of binder include starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols. The binder according to current invention are present in an amount 0.5-10% w/w.
Non-limiting examples of preservatives include one or more of phenoxyethanol, parabens such as methyl paraben and propyl paraben and their sodium salts, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, and mixtures thereof. Non-limiting examples of buffering agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof. Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives. The binder according to current invention are present in an amount 0.1-2% w/w.
Non-limiting examples of polymers include one or more of gum arabic, sodium based lignosulfonate, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, and ethylene glycol dimethacrylate. Polymers also include ionic and non-ionic polymers wherein ionic polymers include cationic or anionic polymers.
Non limiting examples of cationic polymers include chitosan, methacrylic acid-methyl methacrylate copolymer (in an about 1:1 ratio), methacrylic acid-methyl methacrylate copolymer (in an about 1:2 ratio), poly(butyl methacylate-co-2-dimethylaminoethyl methacrylate-co-methyl methacrylate) (in about an 1:2:1 ratio), Eudragit and crosslinked acrylic acid copolymers.
Non limiting examples of anionic polymers include sodium alginate (e.g., Protanal.RTM. LF 120M, Protanal.RTM. LF 200M, Protanal.RTM. LF 200D), sodium carboxymethyl cellulose (CMC), chondroitin sulfate, carrageenan (e.g., Gelcarin.RTM. 209, Gelcarin.RTM. 379), glycosaminoglycans, mucopolysaccharides, pectin, gelatin and hyalouronic acid.
Non-limiting examples of solvents include one or more of water; tetrahydrofuran; alcohols, e.g., methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g., pentane, hexane and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons, e.g., chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride acetates, e.g., ethyl acetate.
The tablets can be coated or uncoated wherein coating can be film coat or functional coat. In one of the embodiment, the coating is of Opadry®.
According to present invention the rate of release of the drug is controlled so that not less than 90% is released in 24hrs. Particularly at least 70% of apremilast is released in 12hrs wherein not more than 50% is released in 4hrs wherein the dissolution is conducted with USP paddle II apparatus at pH 4.5 acetate buffer + 2.0% Tween 80.
Further, the formulation is stable at 250C ± 20C & 60% RH ± 5 % RH and at 300C ± 20C & 75% RH ± 5 % RH and at 400C ± 20C & 75% RH ± 5 % RH.
There is also provided a economical and cost effective process of preparing a controlled release oral composition comprising apremilast or salt thereof, a compressibility agent, a polymer, a swelling agent, a floating agent, and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis; wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose.
The prior art process described in Celgenes US patent No. 9532977B2 uses roller compaction for prepartion of controlled release composition of apremilast. During roller compaction, due to poor flow and poor compressibility of blend, a compact uniform ribbon was not formed i.e. during compaction along with non-uniform ribbon, powder/ blend comes out as such. The Power / Blend again subjected for recomapction through roller compactor, The compaction process repeated multiple cycle to get compact uniform ribbion. This is not economical process and may results in problems such as content uniformity and poor compressibility and hence may compromise the effect of apremilast.
Inventors have found a better process than prior art which involved use of compressbility agents such as hydroxypropylcellulose and hydroxypropylmethyl cellulose. In this process, during roller compaction, a compact uniform ribbon was formed i.e. improved compressibility of blend due to addition of hydroxypropylcellulose or hydroxypropylmethyl cellulose.
A process of preparing a controlled release oral composition comprising apremilast or salt thereof, a compressibility agent, a polymer, a swelling agent, a floating agent, and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis; wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose; wherein said process comprises steps of: (a) mixing and sifting apremilast or salt thereof, the compressibility agent, the polymer, the swelling agent, floating agent and the pharmacutically acceptable excipient to obtain a blend mix; (b) roller compacting above blend to obtain a ribbon which passed through mill to obtain granules; and (c) compressing the granules of step 2 along with other the pharmacutically acceptable excipients to obtain the controlled release oral composition; wherein said process produces a compact uniform ribbon of a blend during roller compaction resulting in imporoved compressibility and content uniformity.
According to embodiments of the present invention, the pharmaceutical formulations disclosed herein can be administered to mammalian subjects, preferably humans, for the treatment of psoriasis, psoriatic arthritis and atopic dermatitis.
WORKING EXAMPLES
EXAMPLE 1:
Composition A B C D
Ingredients mg/tab mg/tab mg/tab mg/tab
Apremilast 75 75 75 75
Amino methacrylate copolymer Eudragit 37.5 37.50 22.50 22.5
Sodium Carboxy methyl cellulose 7L2P 112.5 258.75 112.50 112.50
Sodium Carboxy methyl cellulose 7HX4 37.5 - 37.50 37.50
Hydroxypropyl cellulose EFX 52.5 15.00 15.00 15
Sodium alginate CR8223 114 142.50 114.00 114.00
Sodium alginate CR8133 28.5 - 28.50 28.50
Mannitol 200SD 95.63 51.56 114.375 98.93
Mannitol 25C 80.625 51.56 114.375 98.94
Citric acid 60 60.00 60.00 60
Sodium Bicarbonate 37.5 - -
Potassium bicarbonate 29
Croscarmellose sodium - 37.50 37.50 37.5
Colliodal silicon dioxide 3.75 5.63 3.75 5.63
Mg Stearate 15 15.00 15.00 15
Manufacturing process:
1. Apremilast, Eudragit EPO, Sodium Alginate, Sodium Carboxy Methyl Cellulose, Hydroxy Propyl Cellulose EXF, mannitol 200SD and mannitol 25C were sifted through # 20ASTM and mixed in blender for 10mins.
2. Above blend was passed through roller compactor and flakes obtained passed through mill to get desired fraction.
3. Granules obtained from step 2 were mixed with citric acid, sodium bi carbonate/potassium bicarbonate, colloidal silicon dioxide and magnesium stearate in blender for 10min.
4. Lubricated blend of step 3 was compressed into tablet.
EXAMPLE 2:
Composition E
Ingredients mg/tab
Apremilast 75
Hypromellose 250
Hydroxy propyl cellulose EFX -
Citric acid 60
Sodium Bicarbonate 37.5
Colloidal silicon dioxide 37.5
Lactose 252
Mg Stearate 37.5
MANUFACTURING PROCESSS:
1. Apremilast, Hypromellose, Lactose, colloidal silicon dioxide were sieved through # 20ASTM and mixed in blender for 10mins
2. Blend formed in step 1 was passed through roller compactor and flakes obtained passed through mill to get desired fraction
3. Granules obtained from step 2 were mixed with citric acid, sodium bi carbonate, colloidal silicon dioxide and magnesium stearate in blender for 10min
4. Lubricated blend of step 3 compressed in to tablet.
EXAMPLE 3:
Dissolution data conducted with USP paddle II apparatus at pH 4.5 acetate buffer + 2.0% Tween 80
Time
(hrs) Formulation # B Formulation # C Formulation # D
1 7 8 9
2 14 18 19
4 32 38 38
6 54 59 57
8 70 75 72
12 91 90 91
16 96 94 97
24 94 93 98

EXAMPLE 4:
Composition F G
Ingredients Mg/tab Mg/tab
Apremilast form B 60 60
Amino methacrylate copolymer
Eudragit 30 -
Sodium Carboxy methyl cellulose
(Blanose CMC 7L2P) 90 -
Sodium Carboxy methyl cellulose
(Blanose 7HX4) 30 -
Hydroxypropyl cellulose
HPC Klucel EFX 42 -
Hypromellose - 200
Sodium alginate (Protanal CR8223) 91.2 -
Sodium alginate (Protanal CR8133) 22.8 -
Mannitol (200SD) 76.50 -
Mannitol 25SD 64.5 -
Citric acid 48 48
Sodium Bicarbonate 30 30
Lactose - 201.6
Colliodal silicon dioxide 200 3 30
Magnesium Stearate 12 30

MANUFACTURING PROCESS:
Formulation 6 was manufactured by process as described in Example 1.
Formulation 7 was manufactured by process as described in Example 2.

EXAMPLE 5: Comparison of Instant invention with prior arts
Inventors of the present aplication had practiced example 98 of prior art US Patent no. 9532977B2. The example 98 discloses a gastric retentive tablet formulation of apremilast with certain excipients except compressibility agents such as hydroxypropyl cellulose or hydroxypropyl methyl cellulose. The example 98 formulation and the instant example D was produced by roller compaction as below.
Formulation # 98 (Celgene) -
1. Apremilast, Eudragit EPO, Sodium Alginate, Sodium Carboxy Methyl Cellulose, mannitol 200SD and mannitol 25C were sifted through # 20ASTM and mixed in blender for 10mins.
2. Above blend was passed through roller compactor and ribbon/flakes obtained passed through mill to get desired fraction. During roller compaction, due to poor flow and poor compressibility of blend, a compact uniform ribbon was not formed i.e. during compaction along with non-uniform ribbon, powder/ blend comes out as such. The Power / Blend again subjected for recomapction through roller compactor, The compaction process repeated multiple cycle to get compact uniform ribbion.
Formulation D (Glenmark) -
1. Apremilast, Eudragit EPO, Sodium Alginate, Sodium Carboxy Methyl Cellulose Hydroxy Propyl Cellulose EXF, citric acid, potassium bicarbonate, mannitol 200SD and mannitol 25C were sifted through # 20ASTM and mixed in blender for 10mins.
2. Above blend was passed through roller compactor and ribbon/flakes obtained passed through mill to get desired fraction. During roller compaction, a compact uniform ribbon was formed i.e. improved compressibility of blend due to addition of Hydroxy Propyl Cellulose EXF.

Advantages of Instant composition over the prior art US 9532977B2:
Composition Ex 98 of US 9532977B2 Ex 4 of Instant invention
Compressibility Poor Good
Formation of compact ribbons during roller compaction Formed but after mutiple roller comaction cycles Formed with less number of comaction cycles
Compaction cycles number 8 to 10 1 to 2
Economic perspective of process Time consuming and costly process Efficient and cost effective process

,CLAIMS:CLAIMS
We claim:
1. A controlled release oral composition comprising apremilast or salt thereof, a compressibility agent, a polymer, a swelling agent, a floating agent, and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis; wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose.
2. The controlled release oral composition of claim 1, wherein the apremilast or salt thereof and the hydroxypropylcellulose is present in a weight ratio ranging from 1:0.1 to 1:5.
3. The controlled release oral composition of claim 1, wherein the apremilast or salt thereof and the hydroxypropylmethyl cellulose is present in a weight ratio ranging from 1:1 to 1:10.
4. The controlled release oral composition of claim 1, wherein the apremilast or salt thereof and the hydroxypropylcellulose is present in a weight ratio 1:0.2 or 1: 0.56 or 1: 0.69.
5. The controlled release oral composition of claim 1, wherein the apremilast or salt thereof and the hydroxypropylmethyl cellulose is present in a weight ratio 1:3.33 or 1:2.66.
6. The controlled release oral composition of claim 1, wherein the polymer is selected from cationic polymer and anionic polymer.
7. The controlled release oral composition of claim 6, wherein the cationic polymer is selected from group consisting of chitosan, methacrylic acid-methyl methacrylate copolymer (in an about 1:1 ratio), methacrylic acid-methyl methacrylate copolymer (in an about 1:2 ratio), poly(butyl methacylate-co-2-dimethylaminoethyl methacrylate-co-methyl methacrylate) (in about an 1:2:1 ratio), Eudragit and crosslinked acrylic acid copolymers; and anionic polymer is selected from group consisting of sodium alginate, sodium carboxymethyl cellulose, chondroitin sulfate, carrageenan, glycosaminoglycans, mucopolysaccharides, pectin, gelatin and hyalouronic acid.
8. The controlled release oral composition of claim 1, wherein the swelling agent is selected from the group consiting of poly(hydroxyalkyl-methacrylate), poly(vinyl alcohol), ethylene vinyl alcohol, and their copolymers, poly(ethylene oxide), and cellulose ethers such as, methylcellulose, and sodium carboxymethylcellulose.
9. The controlled release oral composition of claim 1, wherein the floating agent is selcted from the group consiting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, magnesium bicarbonate, calcium bicarbonate and calcium carbonate.
10. The controlled release oral composition of claim 1, wherein the pharmacutically acceptable excipients comprises a binder, diluent, lubricant, disintegrant, glidant and pH modifier.
11. A process of preparing a controlled release oral composition comprising apremilast or salt thereof, a compressibility agent, a polymer, a swelling agent, a floating agent, and a pharmacutically acceptable excipient for the treatment of psoriasis or atopic dermatitis; wherein the compressibility agent is selected from hydroxypropylcellulose and hydroxypropylmethyl cellulose; wherein said process comprises steps of: (a) mixing and sifting apremilast or salt thereof, the compressibility agent, the polymer, the swelling agent, floating agent and the pharmacutically acceptable excipient to obtain a blend mix; (b) roller compacting above blend to obtain a ribbon which passed through mill to obtain granules; and (c) compressing the granules of step 2 along with other the pharmacutically acceptable excipients to obtain the controlled release oral composition; wherein said process produces a compact uniform ribbon of a blend during roller compaction resulting in imporoved compressibility and content uniformity.
12. The process as claimed in claim 11, wherein the apremilast or salt thereof and the hydroxypropylcellulose is present in a weight ratio ranging from 1:0.1 to 1:5.
13. The process as claimed in claim 11, wherein the apremilast or salt thereof and the hydroxypropylmethyl cellulose is present in a weight ratio ranging from 1:1 to 1:10.
14. The process as claimed in claim 11, wherein the apremilast or salt thereof and the hydroxypropylcellulose is present in a weight ratio 1:0.2 or 1: 0.56 or 1: 0.69.
15. The process as claimed in claim 11, wherein the apremilast or salt thereof and the hydroxypropylmethyl cellulose is present in a weight ratio 1:3.33 or 1:2.66.
16. The process as claimed in claim 11, wherein the polymer is selected from cationic polymer and anionic polymer.
17. The process as claimed in claim 16, wherein the cationic polymer is selected from group consisting of chitosan, methacrylic acid-methyl methacrylate copolymer (in an about 1:1 ratio), methacrylic acid-methyl methacrylate copolymer (in an about 1:2 ratio), poly(butyl methacylate-co-2-dimethylaminoethyl methacrylate-co-methyl methacrylate) (in about an 1:2:1 ratio), Eudragit and crosslinked acrylic acid copolymers; and anionic polymer is selected from group consisting of sodium alginate, sodium carboxymethyl cellulose, chondroitin sulfate, carrageenan, glycosaminoglycans, mucopolysaccharides, pectin, gelatin and hyalouronic acid.
18. The process as claimed in claim 11, wherein the swelling agent is selected from the group consiting of poly(hydroxyalkyl-methacrylate), poly(vinyl alcohol), ethylene vinyl alcohol, and their copolymers, poly(ethylene oxide), and cellulose ethers such as, methylcellulose, and sodium carboxymethylcellulose.
19. The process as claimed in claim 11, wherein the floating agent is selcted from the group consiting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, magnesium bicarbonate, calcium bicarbonate and calcium carbonate.
20. The process as claimed in claim 11, wherein the pharmacutically acceptable excipients comprises a binder, diluent, lubricant, disintegrant, glidant and pH modifier.

Dated this 30th day of July 2019
Digitally signed by
Dr. Pramod Sagar
DGM, Intellectual property management
Glenmark Pharmaceuticals Ltd.