Patent Application
20190060221
The present invention relates to a topical formulation comprising apremilast in the treatment of psoriasis, psoriatic arthritis, atopic dermatitis and chronic eczema. The composition of the present invention may be used alone or in combination with other systemic or topical therapies. The present invention also describes a process of producing topical pharmaceutical composition. Topical formulations may include include gels, ointments, creams, solution and foams and processes for their preparation.
Psoriasis is a disease where skin inflammation occurs, manifested by papules and scales, due to an abnormal homeostasis between epidermis and immune system which leads to premature maturation of keratinocytes and inflammatory cell infiltration in the dermis and abnormal hyperproliferation of the skin's epidermal layer (Griffiths et al, Lancet 2007; 370: 263-71). Abnormal epidermal hyperplasia is a major histological manifestation of psoriasis which occurs due to abnormal modulation of angiogenesis pathway VEGF/angiopoietin/Tie pathway by TNF-alpha (Kuroda et al, J Invest Dermatol 2001). In addition, the pathogenesis of psoriasis involves dendritic cells and T-cells, and cytokines like IL-6, IL-8, and IFN-gamma (Davidovici et al, J Invest Dermatol. 2010; 130(7):1785-96), apart from genetic and environmental factors. Most common clinically evident psoriasis is chronic plaque or psoriasis vulgaris. Psoriasis is associated with much comorbidity, of which psoriatic arthritis is most common (Helliwell et al, Ann Rheum Dis 2005).
Based on the pathophysiological understanding, preclinical research and clinical outcome studies, many pharmacological therapies for psoriasis have been identified and developed. They include topical treatments that involve vitamin D and its analogues, corticosteroids, calcineurin inhibitors, dithranol, and tar, phototreatments, and oral or injectable therapies that involve methotrexate, ciclosporin, retinoids, and fumarates. In the recent past, biological agents that target tumour necrosis factors α, interleukin 12, or interleukin 23, have been developed (Griffiths et al, Lancet 2007; 370: 263-71). However, the long-term safe control of psoriasis is limited due to variations in individual responsiveness, comorbidities, and side effects of the existing therapies. In addition, toxicity and patient compliance of the injectable therapies (which include biological agents) remains an issue in the long term therapeutic success.
Phosphodiesterase (PDE) 4 inhibitors are a class of low molecular weight compounds that exhibit anti-inflammatory effects (Spina 2008). Clinically, PDE4 inhibitors have been used for the treatment of various chronic inflammatory diseases, including psoriasis, psoriatic arthritis, atopic dermatitis, and inflammatory bowel disease (Schafer et al 2012). Apremilast is an oral PDE4 inhibitor that works intracellularly to regulate production of pro- and anti-inflammatory mediators implicated in the pathogenesis of psoriasis and psoriatic arthritis. Apremilast is clinically used for the treatment of adult patients with active psoriatic arthritis and for patients with moderate to severe plaque psoriasis (Young et al 2016).
Apremilast is presently available in market under the tread name of OTEZLA® by the Celgene group. OTEZLA® is marketed orally in 10 mg, 20 mg and 30 mg strength. Apremilast is generally well tolerated orally, with the most common adverse events being weight loss, diarrhea, nausea and emesis in the first year of treatment and nasopharyngitis and upper respiratory tract infection with continued treatment (Keating et al 2017). These side effects are dose-limiting and thus the therapeutic potential of apremilast may not be fully realized. To overcome this obstacle, we have utilized the topical route of administration of apremilast with potent and long-lasting local effect and minimal systemic exposure.
WO 2017168433 discloses pharmaceutical composition comprising apremilast and dimethyl sulfoxide. Another application WO 2017216738 discloses topical pharmaceutical composition comprising apremilast and solubilizers like dimethyl isosorbide.
The treatment according to the present invention consists of the topical administration of apremilast at concentrations of 0.01% w/w to 25% w/w , in the form of a gel, lotion, cream or ointment, optionally, also in combination with other active principles such as vitamins D, E and A or derivatives thereof, methotrexate or derivatives thereof, cyclosporine or derivatives thereof, palladium and/or ruthenium or derivatives thereof, anti-inflammatory agents, immunosuppressive agents, antihistamines, monoclonal antibodies and fusion proteins, cytokines and mediators, antibiotic or derivatives thereof, antifungal agents or derivatives thereof, hormones, peroxisome proliferator-activated receptor gamma activators or derivatives thereof, anti-viral agents or derivatives thereof, vegetable and/or animal extracts, phytochemicals or derivatives thereof, zinc pyrithione and/or other essential minerals, phototherapy and cell hyperproliferation modulators.
The present invention discloses a topical formulation comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate. Topical formulations include gel, ointment, creams, solution and foams and process for the preparation thereof. The topical formulations of this invention are therefore suitable for the treatment of psoriasis and psoriatic arthritis.
The main objective of the present invention is to provide topical pharmaceutical composition comprising apremilast present at a concentration of 0.01 to 25% w/w with Isopropyl myristate and optionally with other pharmaceutically acceptable excipients
In a first embodiment is provided topical pharmaceutical composition in a gel form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically excipients and process for the preparation thereof.
In a second embodiment is provided topical pharmaceutical composition in an ointment form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In a third embodiment is provided topical pharmaceutical composition of in a foam form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In a fourth embodiment is provided topical pharmaceutical composition in a solution form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In a fifth embodiment is provided topical pharmaceutical composition of in a cream form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In one of the preferred embodiment is provided a gel formulation comprising apremilast present at a concentration of 0.01% w/w to 10% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In other preferred embodiment, other pharmaceutically acceptable excipients may be selected from thickening agents, solvents, neutralization agent for polymer, vehicle, ointment base, propellant, foaming agent, solubility enhancer and surfactant and the like.
In another embodiment is provided the use of different formulations such as gel, ointment, creams, solution and foams and the like of apremilast present at a concentration of 0.01% w/w to 25% w/w according to the present invention, for the treatment of psoriasis and psoriatic arthritis.
In yet other embodiments are provided topical formulations comprising the apremilast of the present invention in combination with another medicament.
The present invention relates to a topical formulation comprising apremilast or analogs and suitable pharmaceutically acceptable excipients.
The main objective of the present invention is to provide topical pharmaceutical composition comprising apremilast present at a concentration of 0.01 to 25% w/w with a suitable penetration enhancer, optionally with other pharmaceutically acceptable excipients.
In a first embodiment is provided topical pharmaceutical composition in a gel form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically excipients and process for the preparation thereof.
In a first embodiment is provided topical pharmaceutical composition of a gel form comprising apremilast present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate as the penetration enhancer, optionally with other pharmaceutically excipients wherein other pharmaceutically acceptable excipients are thickening agents, neutralizing agents for polymer, vehicle, solvent, etc.
In an embodiment, other excipients such as aliphatic alcohols, monohydric/polyhydric alcohols, and mixtures thereof, can also be used as penetration enhancer.
Thickening agents used may be selected from the group of hydrophilic polymers such as carbomers, carbomer polymer, carbomer derivative (for example carbopol 974P, carbopol 934P, etc.) cellulose derivatives, anionic polymers, polyvinyl alcohol, water soluble polysaccharide may be at least one selected from the group consisting of hyaluronic acid, hyaluronate, poly-γ-glutamic acid, poly-γ-glutaminate, agar, alginic acid, alginate, carrageenan, furcellaran, pectin, arabic gum, karaya gum, tragacanth gum, ghatti gum, guar gum, locust bean gum, psyllium seed gum, gleatin, chitin, dextran, xanthan gum, chitosan, chondroitin-4-sulfate, chondroitin-6-sulfate and starch and suitable mixtures thereof.
Neutralizing agent for polymer used may be selected from the group of polyfunctional amine such as triethanolamine, poly (ethyleneimine), diisopropanolamine, triisopropanolamine, arginine, aminomethyl propanol, tetrahydroxypropyl ethylenediamine, tromethamine; alkali and alkaline earth metal hydroxides such as sodium and potassium hydroxides and lithium hydroxide, ammonium hydroxide and the like or suitable combinations thereof.
The epoxy cross-linking agent may be at least one selected from the group consisting of epichlorohydrin, 1,4-butandiol diglycidyl ether, ethylene glycol diglycidyl ether, 1,6-hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, trimethlypropane polyglycidyl ether, 1,2-(bis(2,3-epoxypropoxy)ethylene, pentaerythritol polyglycidyl ether and sorbitol polyglycidyl ether or their suitable combinations.
Vehicle is selected from purified water, suitable solvent(s) and suitable mixtures thereof.
Solvent used may be selected from the group of pharmaceutically acceptable Glycols (for example, polyethylene glycol, propylene glycol and hexylene glycol), alcohols, polysorbate 40 (a polyhydroxy organic compound), Poloxamer and the like.
General Process of Preparation:
Thickening agent is dissolved in hot water. Separately, apremilast is dissolved in suitable solvent and mixed with dissolved thickening agent. Further neutralization agent and penetration enhancer is mixed and allow to set in gel form.
In a second embodiment is provided topical pharmaceutical composition in an ointment form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In a second embodiment is provided topical pharmaceutical composition of an ointment form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients, wherein such other pharmaceutical excipients are selected from vehicle for active, ointment base, preservative and other suitable pharmaceutically acceptable carriers.
Isopropyl myristate is used as a penetration enhancer. Other excipients such as, monohydric/polyhydric alcohols, and mixtures thereof, can also be used as penetration enhancer. Suitable vehicle is selected from the group of pharmaceutically acceptable glycols (for example, propylene glycol and hexylene glycol, diethylene glycol monoethyl ether) alcohols, polysorbate 40 (a polyhydroxy organic compound), 1,2-, diols, and mixtures thereof.
Ointment bases is selected from the group of hydrocarbon bases (for example, white petrolatum and white ointment), absorption bases (for example, hydrophilic petrolatum and lanolin), water removable bases (for example, hydrophilic ointment also known as cream), water soluble bases (for example, propylene glycol, polyethylene glycol); polyol ethers and such as white wax, stearyl alcohol, cholesterol, cetyl esters wax, and mixtures thereof.
Preservatives are selected from suitable acids such as citric acid, benzoic acid, esters, alcohols such as bronopol chlorobutanol, monothioglycerol, phenols such as cresol, Butylated hydroxylanisol, Butylated hydroxyltoluene, and quaternary ammonium compounds.
General Process of Preparation:
Ointment base is heated and stirred till clear solution is obtained. Separately, apremilast is dissolved in a suitable solvent and added to melted ointment base. Lastly a preservative and isopropyl myristate is added to the solution and allowed to cool till the dispersion to form ointment.
In a third embodiment is provided topical pharmaceutical composition in a foam form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with a suitable penetration enhancer, optionally with other pharmaceutically acceptable excipients and processes for the preparation thereof.
In a third embodiment is provided a topical pharmaceutical composition in a foam form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with a suitable penetration enhancer, optionally with other pharmaceutically acceptable excipients, wherein other pharmaceutical excipients are selected from a propellant, humectant, foaming agent, solubility enhancer for foaming agents, pH modifiers, buffers, hydrotropic agents, solvents and other pharmaceutically acceptable carriers.
According to the invention, isopropyl myristate is used as the penetration enhancer. Other excipients such as aliphatic alcohols, monohydric/polyhydric alcohols, and mixtures thereof, can also be used as penetration enhancer. Propellant may be selected from the group consisting of hydrocarbon, a chlorofluorocarbon dimethyl ether, hydroflourocarbon and mixture thereof.
Foaming agent may be selected from the group of block copolymer, fatty acid ethoxylates, fatty alcohol ethoxylates, polysorbates and glycerol ester ethoxylates and their suitable mixtures.
Solubility enhancer for foaming agents Non Volatile Liquids: Poly Ethylene Glycol 200, Poly Ethylene Glycol 300, Poly Ethylene Glycol 400, Glycerine, Propylene Glycol, fixed oils and their suitable mixtures.
Hydrotropic agents may be selected from suitable aromatic anionics or cationics. Aromatic anionics used may be selected from Sodium benzoate, Sodium salicylate, Sodium benzene sulphonate, Sodium benzene disulphonate, Sodium cinnamate or their suitable mixtures.
Aromatic cationics used may be selected from para amino benzoic acid hydrochloride, Procaine hydrochloride, Caffeine. Aliphatics and linear anionics Sodium alkanoate or their suitable mixtures.
Solvents used may be a polar hydrophilic solvent, which may be selected from the following groups of compounds: (1) polyols (organic solvents that contain at least two hydroxy groups in their molecular structure); and (2) polyethylene glycols (PEGs). The polyols can be selected from the group of di-alcohols, such as propylene glycol, butanediol and diethylene glycol, and tri-alcohols, such as glycerin. The PEGs can be primarily low-molecular weight liquid PEGs, such as PEG 200, PEG 400, PEG 600 and PEG 1000; however, mixes of the liquid PEGs with higher molecular weight such as PEG 4000, PEG 6000, and PEG 8000 .
Secondary polar solvents may be selected from dimethyl isosorbide, ethoxydiglycol, and alpha hydroxy acids, such as lactic acid and glycolic acid.
Highly purified diethylene glycol monoethyl ether (e.g. Transcutol® P) can also be selected as solvent in foam.
pH modifiers can be selected from inorganic salts e.g. calcium chloride; barium chloride; or from acids, especially organic acids, salts, buffering substances, e.g. citric acid, acetic acid, salicylic acid, lactic acid and other alpha hydroxy acids as well as inorganic acids e.g. HCl, NaOH, KOH and other bases. These regulators are used in amounts sufficient to provide the desired pH value of the composition
Buffer may be selected from the group containing citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, formate/formic acid, propionate/propionic acid, lactate/lactic acid, carbonate/carbonic acid and ammonium/ammonia buffer and phosphate buffers.
Aqueous quick breaking foam agent may be selected from C1-C6 alcohol.
General Process of Preparation:
Quick breaking foam is prepared by dissolving Apremilast in solvent/ humectant and solubility enhancer was added by dissolving in water. Further buffer/ pH modifier was added to this with continuous stirring.
In separate vessel foaming agent is melted and mixed with above solution. At last, propellant and Isopropyl myristate is added upon cooling.
In a fourth embodiment is provided topical pharmaceutical composition in a solution form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In a fourth embodiment is provided topical pharmaceutical composition in a solution form comprising apremilast, present at a concentration of 0.01% w/w to 25% w/w with Isopropyl myristate, optionally with other pharmaceutically acceptable excipients; wherein other pharmaceutically acceptable excipients are selected from suitable preservatives, solvent for active, a suitable vehicle and other pharmaceutically acceptable carriers.
Isopropyl myristate is used as the penetration enhancer. Other excipients such as aliphatic alcohols, monohydric/polyhydric alcohols or mixtures thereof, can also be used as penetration enhancer. Preservatives are selected from acids, esters, alcohols, phenols, mercurial compounds and quaternary ammonium compounds.
Solvents for active are selected from 1,2-, diols, polyether compounds and mixtures thereof.
General Process of Preparation:
Solution are prepared by dissolving the apremilast in a solvent as described above, mixing until dissolved, then making up to the desired volume by adding sufficient solvent. Other excipients may be added to the solvent that help stabilize or solubilize the active ingredient, which are well known to a person skilled in the art.
In one of the preferred embodiment is provided a gel formulation comprising apremilast present at a concentration of 0.01% w/w to 10% w/w with isopropyl myristate and optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In specifically preferred embodiment is provided a gel formulation comprising apremilast present at 2.5% w/w, 3.0% w/w and 5.0% w/w concentration with Isopropyl myristate and optionally with other pharmaceutically acceptable excipients and process for the preparation thereof.
In another preferred embodiment, other pharmaceutically acceptable excipients may be selected from thickening agents, solvents, neutralization agent for polymer, vehicle, ointment base, propellant, foaming agent, solubility enhancer and surfactant, etc.
Isopropyl myristate is used as a Penetration enhancer.
Thickening agents used may be selected from the group of hydrophilic polymers such as carbomers, carbomer polymer, carbomer derivative (for example carbopol 974P, carbopol 934P, etc.) cellulose derivatives, anionic polymers, polyvinyl alcohol, water soluble polysaccharide may be at least one selected from the group consisting of hyaluronic acid, hyaluronate, poly-γ-glutamic acid, poly-γ-glutaminate, agar, alginic acid, alginate, carrageenan, furcellaran, pectin, arabic gum, karaya gum, tragacanth gum, ghatti gum, guar gum, locust bean gum, psyllium seed gum, gleatin, chitin, dextran, xanthan gum, chitosan, chondroitin-4-sulfate, chondroitin-6-sulfate and starch and mixtures thereof, preferably carbomer derivatives.
Neutralizing agent for polymer used may be selected from the group of polyfunctional amine such as triethanolamine, poly (ethyleneimine), diisopropanolamine, triisopropanolamine, arginine, aminomethyl propanol, tetrahydroxypropyl ethylenediamine, tromethamine; alkali and alkaline earth metal hydroxides such as sodium and potassium hydroxides and lithium hydroxide, ammonium hydroxide and the like, preferably triethanolamine.
Vehicle is selected from purified water, solvent and mixture thereof.
Solvent used may be selected from the group of pharmaceutically acceptable Glycols (for example, polyethylene glycol, propylene glycol and hexylene glycol), alcohols, polysorbate 40 (a polyhydroxy organic compound), Poloxamer, preferably polyethylene glycol and propylene glycol.
General Process of Preparation:
Gel is prepared by dissolving (i) 1.5% w/w thickening agent in hot water at 70° C. and (ii) 0.01-10% w/w apremilast in solvent (or mixture of solvent) and then mixing (i) and (ii) to make solution (iii). To the solution of step (iii) 0.75% w/w neutralizing agent for polymer and 4.0% w/w penetration enhancer is added and allowed it to set in gel form.
The formulations of the present invention such as the gel, ointment, creams, solution and foams of apremilast can be used for the treatment of psoriasis and psoriatic arthritis.
In another further embodiment the topical formulation of the invention described above may optionally be combined with another medicament. In an embodiment, the pharmaceutical composition as described above can be combined with vitamins D, E and A or derivatives thereof, methotrexate or derivatives thereof, cyclosporin or derivatives thereof, palladium and/or ruthenium or derivatives thereof, anti-inflammatory and immunosuppressive agents inclusive of (but not limited to JAK inhibitors, IKK-TBK inhibitors, PDE3 AND PDE4 inhibitors), antihistamines, monoclonal antibodies and fusion proteins, cytokines and other hormone mediators, antibiotic or derivatives thereof, antifungal agents or derivatives thereof, hormones, peroxisome proliferator-activated receptor gamma activators or derivatives thereof, NSAIDs or analogs thereof, anti-viral agents or derivatives thereof, vegetable and/or animal extracts, phytochemicals or derivatives thereof, zinc Pyrithione and/or other essential minerals, phototherapy and cell hyperproliferation modulators.
The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Process for the Preparation of Apremilast Gel
1. Heat Purified water upto 70° C. and dissolve Carbopol 974P in it under stirring.
2. Heat Polyethlyene glycol/propylene glycol upto 50° C. and dissolve Apremilast in it.
3. Add solution of step 2 to step 1 under stirring and allow to stir well.
4. Add Triethanolamine and Isopropyl myristate to step 3 under stirring and allow to stir till gel formation.
5. Allow to cool the gel and fill in Aluminum tubes.
Process for the Preparation of Apremilast Ointment:
(i) Heat White petrolatum upto 60° C. to form clear solution.
(ii) Stir solution of step 1.
(iii) Dissolve/disperse apremilast in transcutol/mineral oil and add to step 2 under stirring.
(iv) Add butylated hydroxy anisole and isopropyl myristate to step 3 under stirring.
(v) Allow to cool the dispersion to form ointment and then fill in Aluminum tubes.
Process of Apremilast Quick Breaking Foam
(i) Heat Propylene glycol up to 50° C. and dissolve Apremilast in it.
(ii) Dissolve Polysorbate 80 in purified water under stirring.
(iii) Step 2 added step 1 under continuous stirring.
(iv) Added potassium hydroxide solution in step 3 under continuous stirring.
(v) In a separate vessel, melt together cetyl alcohol & steryl alcohol and heat to 75° C.
(vi) Add the later mixture to the aqueous phase with continuous stirring.
(vii) When cooled to 40° C. mix the dehydrated alcohol, propane, butane, isopropyl myristate, and added slowly to the emulsion with stirring and discontinue stirring when temperature reached to 30°.
Process for the Preparation of Apremilast Solution
1. Heat Propylene glycol upto 50° C. and dissolve Apremilast in it.
2. Dissolve butylated hydroxy anisole in polyethylene glycol under continuous stirring.
3. Step 2 added step 1 under continuous stirring.
4. In a separate vessel added isopropyl myristate in purified water under stirring.
Solution of step 4 was added to solution of step 3 under continuous stirring
Biological Studies
Animal:
Six to eight week old male C57BL6/J mice were obtained from the Animal Research Facility of Zydus Research Centre, Ahmedabad, India. They were housed in ventilated cages, in an air conditioned room with relative humidity 55±10%, subjected to 12 h dark/light cycles and given free access to food and water. The procedures for animal use and experimentation were reviewed and approved by Institutional Animal Ethics Committee (as per CPCSEA, Committee for the Purpose of Control and Supervision of Experiments on Animals, Government of India) of Zydus Research Centre, which is an AAALAC accredited facility.
Protocol:
Observation:
Conclusion:
Gel formulations of 6 mg and 10 mg concentration have shown superior results
Pharmacokinetics of apremilast in male C57BL6/J mice
Pharmacokinetics of apremilast was studied in male C57BL6/J mice by topical route. Two day before treatment, mice hair was removed from the dorsal regions and test area (1.5 cm2) was marked. Total eighteen mice were randomly divided in six groups (n=3). The formulation was applied to the test area at an amount of 1 mg/cm2 and dermis was collected at each time points i.e. 0.5, 1, 2, 4, 8 and 24 hours post administration.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201721029757 | Aug 2017 | IN | national |
