Novel synergistic topical pharmaceutical composition of tapinarof

Abstract

Novel synergistic topical pharmaceutical composition of Tapinarof This invention relates to a novel synergistic topical pharmaceutical composition of Tapinarof formulated with functional excipients containing a combination of polyethers (PEG 400 and PEG 4000), PLGA, and 4-chlororesorcinol for the treatment of psoriasis. Tapinarof acts by modulating aryl hydrocarbon receptors and reducing pro-inflammatory cytokine production. The selected excipients enhance drug penetration, stability, and therapeutic efficacy. Polyethylene glycols provide humectant, anti-inflammatory, emollient, and penetration-enhancing properties, while PLGA minimizes irritation and burning, offering a soothing, sustained-release effect. 4- Chlororesorcinol confers antioxidant and photoprotective benefits, preventing UV-induced skin damage. As evident from animal study synergistic formulation showed enhanced keratolytic and anti-inflammatory activity, promoting better resolution of hyperkeratotic psoriatic lesions. This non-steroidal, anti-inflammatory, and UV-protective formulation provides a more effective therapeutic alternative for the management of chronic psoriatic inflammation.

Description

[0001] Medrenova-202441087065

[0002] 1

[0003] TITLE OF THE INVENTION

[0004] Novel synergistic topical pharmaceutical composition of Tapinarof

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to a novel synergistic topical pharmaceutical composition and method of preparation thereof for the treatment of skin diseases namely psoriasis, wherein the said novel composition contains aryl hydrocarbon receptor agonist (AhR Agonist) - Tapinarof and functional excipients as combination of polyethers: polyethylene glycol (PEG), Poly(lactic-co- glycolic acid) i.e PLGA along with other excipients. The invented formulation is non-steroidal, anti-inflammatory & Keratolytic that enables easy penetration of active component through stratum comeum. It also protects the skin from damaging effects of UV radiation thereby protecting keratinocytes & restoring the barrier function of the skin.

[0007] BACKGROUND AND PRIOR ART

[0008] Tapinarof is a non-steroidal aryl hydrocarbon receptor (AhR) agonist.

[0009] Tapinarof is 3, 5-dihydroxy-4-isopropyl- / ra / / .s-stilbene, also known as (E)-2-isopropyl-5- styrylbenzene-l,3-diol, with the empirical formula C17H18O2, a molecular weight of 254.32, and the following structural formula.

[0010]

[0011] Tapinarof (VTAMA) is approved for its use in Plaque Psoriasis and Atopic Dermatitis in US. VTAMAis a 1% cream formulation comprising benzoic acid, butylated hydroxytoluene, citric acid monohydrate, diethylene glycol monoethyl ether, edetate disodium, emulsifying wax, mediumchain triglycerides, polyoxyl 2 stearyl ether, polyoxyl 20 stearyl ether, polysorbate 80, propylene glycol, purified water, and sodium citrate dihydrate.

[0012] US10195160, US10426743, US11458108, US11612573 and US11622945 are listed in orange book (US) and relate to formulation of Tapinarof that is an oil-in-water emulsion. These listed patents are family equivalents.

[0013] US10647649 and US11597692 highlight the process of synthesis of active i.e Tapinarof.

[0014] US11590088 relates to method of treating mild to severe plaque psoriasis with 1% topical composition of Tapinarof.

[0015] US11617724 relates to stable oil in water emulsion composition for topical administrationMedrenova-202441087065

[0016] 2

[0017] US11497718 and US11938099 relates to method of treating mild to severe atopic dermatitis with 1% topical composition of Tapinarof.

[0018] Crystalline polymorph of Tapinarof and its pharmaceutical compositions are disclosed in W02023067606A1.

[0019] Solid state forms of Tapinarof, including crystalline polymorphs and co-crystals, along with processes for preparation thereof, and pharmaceutical compositions thereof are disclosed in US20240208889.

[0020] Rectal formulation of Tapinarof for treatment of anal, rectal or distal gastrointestinal (GI) disorders that can be addressed through rectal administration are described in WO2020212982. The disclosed composition also includes an additional active agent selected from a group of an antiinflammatory, an immuno-suppressant, an antibiotic, a local anaesthetic and a combination thereof.

[0021] Composition comprising Tapinarof for the treatment of pruritus are disclosed in US20210346279, wherein polyethylene glycol is used as a penetration enhancer. The composition is intended for treatment of pruritus which is not associated with psoriasis.

[0022] Compositions of Tapinarof for treatment of an ocular inflammatory disease or ocular degenerative diseases by ophthalmic administration of a composition comprising of tapinarof and optionally at least one additional active agent are disclosed in US20220071924.

[0023] Compositions that include Tapinarof and an additional AHR agonist are disclosed in WO2021059281.

[0024] The composition includes Tapinarof and a second active agent which is selected from the group consisting of adalimumab, secukinumab, guselkumab, ixekizumab, etanercept, infliximab, ustekinumab, golimumab, apremilast, a topical corticosteroid, prednisone, vitamin D, calcipotriene, calcitriol, betamethasone dipropionate, anthralin, methotrexate, cyclosporine, vitamin A, a retinoid, tazarotene, acitretin, a calcineurin inhibitor, tacrolimus, pimecrolimus, thioguanine, hydroxyurea, salicylic acid, coal tar, and combinations thereof is disclosed in US20230106782.

[0025] The composition of Tapinarof in the form of an oil-in-water emulsion is disclosed in WO2024192355. In the said disclosure, the oil phase is comprised of medium chain triglycerides, propylene glycol, non-ionic emulsifying wax, di ethylene glycol monoethyl ether, polyoxyl stearyl ether-2, polysorbate 80, polyoxyl stearyl ether-20, benzoic acid, and butylated hydroxy toluene. The aqueous phase is comprised of sodium citrate, edetate disodium, citric acid monohydrate, and water.

[0026] The composition of Tapinarof containing a surfactant is disclosed in US20230346716, wherein the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80,Medrenova-202441087065

[0027] 3

[0028] sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers and combination thereof.

[0029] WO2021100051 discloses the treatment of skin disorders with topical compositions comprising Tapinarof and a PDE4 inhibitor. The PDE4 inhibitor is selected from roflumilast, roflumilast N-oxide, apremilast, crisaborole, rolipram, cilomilast, ibudilast, piclamilast, pharmaceutically acceptable salt, and combinations thereof.

[0030] WO2022109626 discloses gel, ointment, and foam formulations of Tapinarof wherein the formulation is either an aqueous or anhydrous gel.

[0031] A topical combination composition comprising tapinarof, tazarotene, a corticosteroid and a suitable carrier for topical administration has been disclosed in W02020174467.

[0032] Tapinarof-EGFR inhibitor compositions are disclosed in US 20220142944 wherein the composition is formulated as a cream, an ointment, a gel, a lotion, a shampoo, a spray, a patch or a foam.

[0033] Topical compositions of Tapinarof and methods for using them to treat mild to moderate atopic dermatitis are disclosed in US 20220287989.

[0034] The topical composition of Tapinarof is disclosed in US20200147000 wherein the topical composition is an oil-in-water emulsion. The oil phase of an emulsion is selected from medium chain triglycerides, propylene glycol, non-ionic emulsifying wax, diethylene glycol monoethyl ether, polyoxyl stearyl ether-2, polysorbate 80, polyoxyl stearyl ether-20, benzoic acid, and butylated hydroxytoluene.

[0035] WO2024013741 discloses topical composition that contains tapinarof or a pharmaceutically acceptable salt thereof along with 1% w / w of a surfactant, wherein the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers and combination thereof.

[0036] Additionally, the disclosed composition includes a gelling agent, an anti-oxidant, and a penetration enhancer. Penetration enhancer used in the composition is selected from options such as dimethylsulfoxide, diethylene glycol monoethyl ether, methyl sulfonylmethane, propylene glycol, dimethyl isosorbide, oleic acid, oleyl alcohol, ethanol, isopropyl alcohol, a polyethylene glycol, hexylene glycol, glycofurol, isopropyl myristate, glycerin, mono- and di- carboxylic acid esters and any combination thereof.

[0037] WO2020188575 discloses a topical combination-composition for the treatment of rosacea comprising at least one acaricidal active agent, at least one essentially non-acaricidal anti-Medrenova-202441087065

[0038] 4

[0039] inflammatory active agent, and a carrier suitable for topical administration, wherein the acaricidal active agent is selected from ivermectin, permethrin, niclosamide, benzoyl peroxide, tapinarof and combinations thereof. The disclosed combination composition is optionally further comprising a vasoconstrictor.

[0040] Tapinarof composition for the treatment of cutaneous adverse effects caused by oncological therapy is disclosed in WO2021059283. The composition includes penetration enhancer which is selected from dimethylsulfoxide (DMSO), methyl sulfonylmethane (MSM), propylene glycol, dimethyl isosorbide, isopropyl myristate, and combinations thereof.

[0041] A combination composition of Tapinarof is disclosed in W02020194313 for treatment, prevention, and / or amelioration of hidradenitis suppurativa, which contains at least one additional active agent selected from an antibiotic, a retinoid, azelaic acid, benzoyl peroxide and combinations thereof, and a suitable carrier.

[0042] WO2021014447 discloses Tapinarof-EGFR inhibitor composition wherein EGFR inhibitor is selected from erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib and combinations thereof.

[0043] A topical composition comprising at least one of a PDE4 inhibitor, a JAK inhibitor, an AhR modulator, or any combination thereof is disclosed in WO2022259252, wherein at least one of the AhR modulator is Tapinarof.

[0044] WO2021014453 discloses a synergistic composition comprising at least one Janus kinase inhibitor (JAK inhibitor) and at least one additional active agent selected from benzoyl peroxide (BPO), at least one retinoid, tapinarof, at least one antibiotic, at least one antiandrogen, at least one acaricide and combinations thereof. The composition is accompanied by a carrier suitable for topical administration.

[0045] W02020136650 describes a topical composition comprising at least one EGFR inhibitor selected from the group consisting of erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib and combinations thereof, wherein Tapinarof is one of the additional active ingredients.

[0046] WO2022094174 reveals the use of Tapinarof in a food additive composition for treatment of esophageal conditions.

[0047] A composition comprising Tapinarof in combination with Ruxolitinib, Deuterated Ruxolitinib, or a pharmaceutically acceptable salt thereof is disclosed in W02022107131.

[0048] A composition containing Tapinarof in combination with EGFR inhibitor and a vasoconstrictor compound has been disclosed in US20210315834. The EGFR inhibitor is selected from erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib, and combinations thereof. The vasoconstrictor compound is selected from oxymetazoline,Medrenova-202441087065

[0049] 5

[0050] xylometazoline, brimonidine, a vasopressin analog, epinephrine, norepinephrine, phenylephrine (Sudafed PE), dopamine, dobutamine, and a serotonin 5-hydroxytryptamine agonist (a triptan). The claimed composition is useful for prevention and treatment of alopecia and hair loss e.g. when such conditions are caused by chemotherapy, radiation therapy or hormone replacement therapy. Topical compositions comprising EGFR inhibitors for treatment of hair loss disorders are disclosed in WO2021084541, wherein Tapinarof is one of the additional ingredients used along with EGFR inhibitors.

[0051] Atopical ophthalmic composition of Tapinarof is disclosed in WO2020255135, said composition contains an additional active agent selected from a weak corticosteroid, an immuno-suppressant, an immuno-modulator, an antimuscarinic agent, a VGF inhibitor, an NSAID, a cytotoxic drug, a corticosteroid-sparing immunosuppressant, a TNF-a inhibitor, an antibiotic, and combinations thereof.

[0052] WO2021214762 discloses the preparation of metal or ammonium salts of Tapinarof to enhance skin penetration and facilitate extended release of this drug. Preparation of silver, copper, zinc, and choline salts of Tapinarof is disclosed. The salts were formulated into ointment and cream topical carriers and in Lipid or PLGA microspheres for extended release after application.

[0053] W02020152690 discloses combination composition comprising Tapinarof along with one additional active agent selected from at least one corticosteroid of potency class 1 or 2, at least one corticosteroid of potency class 3-7, calcipotriene, at least one JAK1, JAK2 or JAK 1 / 2 inhibitor and combinations thereof, and a carrier suitable for topical administration.

[0054] W02024011189 discloses methods of treating disease using ANTI-IL1RAP antibodies and antibody-drug conjugates, wherein Tapinarof is one of the options of therapeutic agents used therein.

[0055] EP4206196 discloses pyrimidine-substituted derivatives as TYK2 inhibitors, wherein one of the options is the use of Tapinarof as a combinable agent along with pyrimidine substituted derivatives. A combination product comprising a carboxamide substituted derivative is disclosed in WO2021204626, wherein Tapinarof is one of the options used in combination.

[0056] OBJECTS OF INVENTION

[0057] It is an object of invention to provide a novel synergistic topical composition of Tapinarof for the treatment of psoriasis and atopic dermatitis;

[0058] Another object of the invention is to provide a non-steroidal composition of Tapinarof that is antiinflammatory;

[0059] Yet another object of invention is to enhance the keratolytic action of TapinarofMedrenova-202441087065

[0060] 6

[0061] Another object of invention is to provide a synergistic composition of Tapinarof with enhanced penetration through stratum comeum;

[0062] Yet another object of the invention is to provide a synergistic composition of Tapinarof that will protect the skin from UV radiation of sunlight;

[0063] SUMMARY OF INVENTION

[0064] Tapinarof is a unique, nonsteroidal compound that works directly on the skin without causing systemic side effects or interactions with other medications.

[0065] The invented synergistic composition of Tapinarof is not only non-steroidal and anti-inflammatory, but it also facilitates enhanced penetration of active components through stratum corneum. Additionally, it also protects skin from UV radiation thereby preventing the damage caused by free radicals that may affect keratinocytes & disrupt the barrier function of the skin.

[0066] Tapinarof by virtue of its AhR receptor agonist action, reduces the production of inflammatory cytokines like IL-17A, IL-17F, IL-22, IL-23 A, and IL-ip.

[0067] Inventors of the present invention have found that polymers of Ethylene Glycol (PEG) act synergistically with the action of Tapinarof in terms of efficacy against psoriasis. PEG has been shown to have action against the allergic component of atopic dermatitis as demonstrated in randomized controlled clinical trials. Application of PEG to skin helps improve the appearance of psoriasis skin lesions and reduce skin thickness in psoriatic mouse models. It can also slow down the growth of skin cells (keratinocytes) and lowers the level of certain inflammatory cytokines (like IL-23, IL-22, IL-6, IL-17C, IL-17F, S100A7, S100A8, S100A9, CXCL1, CXCL2, and IL-1P) in the affected skin. This happens by reducing the number of certain immune cells, including myeloid-derived suppressor cells (MDSCs) and T helper 17 (Thl7) cells.

[0068] PLGA Poly (lactic-co-glycolic acid) aids in reducing the irritation and burning sensation and soothes the skin.

[0069] 4- chlororesorcinol acts as an antioxidant and neutralizes free radicals caused by oxidative stress, thereby preventing UV-induced skin damage. It has anti-inflammatory properties. In addition, it also reduces hyper-pigmentation caused by UV exposure.

[0070] Individual components of the invented formulation are known in the art. However, the selected unique combination offers multiple advantages and synergy.

[0071] The synergistic effect in the said combination is proven by means of a pre-clinical study wherein a group of mice treated with combination formulation of Tapinarof, PEG and PLGA compared to Tapinarof alone produced comparably greater mitigation, normalized epidermal thickness, restored body weight, penetrated deep into dermis suppressing inflammation in perifollicular area,Medrenova-202441087065

[0072] 7

[0073] and resulted in the maximum decline in PASI scoring as observed in imiquimod-induced psoriasis mouse model.

[0074] BRIEF DESCRIPTION OF DRAWINGS AND GRAPHS

[0075] Fig 1: Histopathological slides showing reduced inflammation in treatment group F (Tapinarof + PEG + PLGA) when compared to Group C (GC -Plain Tapinarof) and normalization as compared Group A (Normal control)

[0076] Graph 1 : Induration of psoriatic lesions in mice after treatment with formulation in Group C (GC-Plain Tapinarof), Group F (Tapinarof + PEG + PLGA) and no treatment group B (GB).

[0077] Graph 2: Erythema in psoriatic lesions in mice after treatment with formulation in Group C (GC-Plain Tapinarof), Group F (Tapinarof + PEG + PLGA) and no treatment group B (GB).

[0078] Graph 3 : Scaling in psoriatic lesions in mice after treatment with formulation in Group C (GC-Plain Tapinarof), Group F (Tapinarof + PEG + PLGA) and no treatment group B (GB).

[0079] Graph 4: Cumulative PASI Score in mice after treatment with formulation in Group C (GC -Plain Tapinarof), Group F (Tapinarof + PEG + PLGA) and no treatment group B (GB).

[0080] Graph 5: Body weight in mice after induction of psoriasis using Imiquimod and treated with formulation Group C (GC -Plain Tapinarof) vs Group F (-Tapinarof + PEG + PLGA); enhanced formulation, on the background of no treatment group B (GB).

[0081] DETAILED DESCRIPTION OF INVENTION

[0082] Embodiments are provided so as to fully convey the scope of the present disclosure to the person skilled in the art. The details provided in the embodiments should not be construed to limit the scope of the present disclosure.

[0083] As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise.

[0084] The terms "comprises," "comprising," “including,” and “having,” “contains” are open-ended transitional phrases.

[0085] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed elements.

[0086] The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.

[0087] The present invention is proposed for topical administration or delivery. As highlighted in the present invention, topical delivery refers to application to the skin or mucous membrane with aMedrenova-202441087065

[0088] 8

[0089] primary aim to have localized action and thus minimizing the systemic absorption and related side effects.

[0090] Most preferred topical dosage forms are: aerosol, cloth, cream, disc, dressing, emulsion, foam, films, gel, jelly, lotion, liniment, liposomes, microneedles oil, ointment, paste, patch, powder, shampoo, soap, solution, sponge, spray, suspension, swab, system and tape.

[0091] The topical dosage form may be administered conventionally or by means of a device.

[0092] In an embodiment, the present composition is a topical gel.

[0093] In an embodiment, the present composition contains of an effective amount of AhR agonist namely, Tapinarof.

[0094] The active substance i.e Tapinarof is present in the concentration of 1% w / w. This concentration of active is known and as used in the approved cream formulation of Tapinarof.

[0095] In an embodiment, the present composition is a PEG based gel formulation for topical administration comprising 1% Tapinarof.

[0096] In an embodiment, the present composition contains one or more functional excipient / s.

[0097] The functional excipients are added to increase the efficacy or potency of other ingredients in the composition.

[0098] The preferred functional excipient in the present invention is polyethylene glycol (PEG) / Macrogols / polyoxyethylene glycol. It is a widely used excipient in topical formulations owing to its non- toxic nature. Polyethylene glycols are stable, hydrophilic substances that are essentially non-irritant to the skin.

[0099] It acts as a humectant and aids in moisturizing and hydrating the skin by absorbing water from the environment and locking the same in skin layers.

[0100] It is an excellent emollient that smoothens the skin surface.

[0101] It also acts as a solvent / co solvent and aids the dissolution of actives as well as other excipients thus making them easier to apply to the skin.

[0102] It is a well- known penetration enhancer that enhances the penetration of active ingredients in to the skin more effectively.

[0103] In an embodiment, the present invention includes a combination of PEG 400 and PEG 4000. PEG 400: It is a clear, colourless and viscous liquid and a low molecular weight. It mainly functions as a solvent, humectant and lubricant.

[0104] In an embodiment, the present invention contains PEG 400 in the concentration range of 10.00 % w / w - 70.00%w / w, more preferably in the range of 40.00 % w / w to 60.00% w / w, more preferably 52.00- 57.00 % w / w, most preferred being 55% w / w.

[0105] PEG 4000: white to off white flaky solid with approx, mol weight of 3100-4010. It mainly functions as moisturiser, emulsifier, stabilizer and enhances the spreadability of the formulation.Medrenova-202441087065

[0106] 9

[0107] In an embodiment, the present invention contains PEG 4000 in the concentration range of 10.00 % w / w - 65.00%w / w, more preferably in the range of 20.00 % w / w to 45.00% w / w, most preferred being 25.00% w / w.

[0108] In an embodiment, the present invention includes PEG 400 and PEG 4000 in the concentration as follows: PEG 400: 55 %w / w and PEG 4000: 25.00% w / w.

[0109] In an embodiment, the composition contains another functional excipient namely: Poly Lactic-co-Glycolic Acid (PLGA).

[0110] It is a biodegradable polymer. It breaks down into safe substances, lactic acid and glycolic acid, and it has been approved by the US FDA and the European Medicines Agency for use in topical preparations.

[0111] It acts as a penetration enhancer and as the polymer breaks down, local pH decreases resulting in enhanced drug absorption by human skin.

[0112] It also aids in reducing the irritation and burning sensation and soothes the skin.

[0113] In an embodiment, the present invention consists of PLGA in the range of 0.5-l%w / w.

[0114] In an embodiment, the composition contains yet another functional excipient namely: 4-chlororesorcinol

[0115] Exposure to UV light (ultraviolet light), specifically UVB (Ultraviolet B), has both therapeutic and harmful effects on psoriatic skin. Addition of 4-chlororesorcinol to the topical composition, ensures therapeutic benefits of UVB, while preventing the harmful effects of UVB on the psoriatic skin.

[0116] UVB light imparts an immunosuppressive effect on the skin which helps in reducing the hyperactivity of T-cells and other immune cells involved in the inflammatory response in psoriasis. The reduction in immune cell activity leads to fewer cytokines (inflammatory mediators) which results in reduced inflammation. UVB light also helps to prevent abnormal accumulation of cells happening due to psoriasis by helping to remove the abnormal skin cells that accumulate in psoriatic plaques by triggering apoptosis.

[0117] On the other hand, psoriatic skin can be more sensitive to UV radiation which may lead to sunburn and skin damage. People with psoriasis who undergo long-term UV phototherapy treatments may have a higher risk of skin cancer.

[0118] 4-Chlororesorcinol does not prevent exposure to UV radiation thus maintaining the benefits of UV, at the same time it prevents the harmful effects of exposure to UV radiation. It acts as an antioxidant and neutralizes free radicals caused by oxidative stress, thereby preventing UV-induced skin damage. It has anti-inflammatory properties. In addition, it also reduces hyperpigmentation caused by UV exposure.Medrenova-202441087065

[0119] 10

[0120] Thus, 4-chlororesorcinol allows therapeutic effects of UV radiation and at the same time, preventing harmful effects by the abovementioned mechanism.

[0121] In an embodiment, the present composition contains 4-chlororesorcinol in the range of 0.1-0.5%w / w.

[0122] In an embodiment, the present composition contains a solvent / s or co- solvents. They help to solubilise the actives and said other excipients to form a homogenous system.

[0123] Solvents may be selected from water, alcohol (ethanol), propylene glycol, polyethylene glycols (PEGs), MCT (Medium chain triglycerides), Dimethyl Sulfoxide (DMSO), N-methyl-2-pyrrolidone, Glycofurol, Solketal, Glycerol, Acetone, Glycerin, oils ( olive oil, soybean oil, canola oil, rapeseed oil, cottonseed oil, coconut oil, palm oil, sesame oil, sunflower oil, safflower oil, rice bran oil, borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil, com oil, flaxseed oil, wheat germ oil, rape seed oil, evening primrose oil, rosehip oil, tea tree oil, melaleuca oil and jojoba oil) , benzyl benzoate, N-N dimethyl acetamide, cetyl alcohol, stearyl alcohol, benzyl alcohol, polyoxyethylene lauryl alcohol, l-3butylene glycol, glycerol and combinations thereof.

[0124] In an embodiment, the solvent used to solubilize the active in the present composition is Propylene glycol in the range of 5-80% w / w.

[0125] In an embodiment, the present composition contains an antioxidant. Antioxidants prevent oxidative degradation of the composition. The antioxidant is selected from the group consisting of butylated hydroxytoluene, ascorbic acid, ascorbic palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-fe / f- butylphenol, erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, sodium bisulphite, Sodium metabisulphite, Sodium thiosulphate, tocopherol, or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.

[0126] Topical formulations are highly susceptible to oxidative degradation when exposed to air or light, leading to stability issues. To ensure stability, sodium metabisulfite can be added to the composition. It can maintain the stability under slightly acidic conditions which are found in human skin. Sodium metabisulfite is more effective at preventing oxidative damage in low pH environments. Even though too much reactive oxygen species (ROS) can damage the body, sodium metabisulfite can be used in topical composition to prevent oxidative degradation when exposed to air.

[0127] In an embodiment, the preferred antioxidant is sodium metabisulfite in the range of 0.1-1% w / w.

[0128] Example 1:

[0129] Development of Topical gel formulation comprising Tapinarof and functional excipients.Medrenova-202441087065

[0130] 11

[0131]

[0132] Manufacturing Process:

[0133] 1. Weigh accurate quantity of PEG 400 in a small vessel and heated upto 70°C (60°C -80°C) observed temperature with constant stirring then weighed quantity of PEG 4000 was added in this vessel under continuous stirring (heating was continued to maintain temp 70°C).

[0134] 2. Accurately weighed quantity of 4-chlororesorcinol were added to hot mix (70°C) with constant stirring to dissolved.

[0135] 3. Hot melt was allowed to cool under continuous stirring approximately 50°C then add accurate quantity of PLGAin step 2 under continuous stirring.

[0136] 4. Propylene glycol was added to step 3 under continuous stirring and mixture was mixed for 5 min.

[0137] 5. Weighed accurate quantity of Sodium metabisulfite and dissolved in 2 mL of water to form clear solution then add in step 4.

[0138] 6. After stirring for approx. 1 hour at temperature 40-45°C solution was started to become more viscous.

[0139] 7. Weighed accurate quantity of Tapinarof was added in step 9 and continuous stirring for 1 hour and stainless steel beaker was kept on cold water bath with continuous stirring. Physico- chemical analysis of the batches:

[0140]

[0141] Medrenova-202441087065

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[0143] &

[0144]

[0145] Analysis of the formulation

[0146] The batches were analysed to determine the assay so as to establish the stability of API in the presence of various chosen excipients:

[0147] HPLC (high-performance liquid chromatography) method for assay of Tapinarof 1% w / w topical gel.

[0148] HPLC Chromatographic Condition

[0149]

[0150] Calculation:

[0151] &

[0152] < >

[0153]

[0154] Medrenova-202441087065

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[0156]

[0157] Example 2:

[0158] Evaluation of effect of Tapinarof Gel with Functional Excipients on Imiquimod- induced psoriasis mouse model

[0159] Animal preparation

[0160] An approximate area of 4.5 cm2at the back of the animals was shaved using hair clippers, followed by the application of depilation cream 24 hrs prior to the application of IMQ cream. After the depilation, the surface of the depilated skin was thoroughly cleaned with water. The prepared skin area was disinfected prior to the procedure using 70% IPA, followed by autoclaved water. Any hair growth during the in-life phase of the study was removed similarly.

[0161] Disease induction

[0162] IMQ (Imiquimod) cream was topically applied to all the animals in groups B, C, D, E, F, and G at -62.5 mg / animal for 7 days on to the shaved surface on the back, during induction phase, body weight, erythema, skin thickness and scaling scores were recorded and cumulative PASI score was determined.

[0163] Treatment

[0164] On day 7, based on the cumulative PASI score, animals were randomized within B, C, D, E, F, and G groups to have similar mean scores. Treatment was initiated starting from day 8, animals in group A to group G topically received the test samples G1 to G7 respectively.

[0165] Dose Selection and Treatment

[0166]

[0167] Medrenova-202441087065

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[0169]

[0170] Observations:

[0171] Clinical Signs, Moribundity, and Mortality

[0172] Mortality and moribundity were assessed during acclimatization and during the pre-randomization phase once daily. Clinical signs other than PASI were observed at least once daily during the inlife phase of the study and the observations were recorded.

[0173] Psoriasis Area Severity Index (PASI) Score Evaluation

[0174] During the study, the visual examination of the following three parameters, erythema (redness), induration (thickness), and desquamation (scale), PASI scores on the back skin of each mouse were recorded daily for 15 days. Skin thickness (mm) was measured daily once by using a Vernier calliper by the tent method. Each parameter was given a score between 0 and 4 (0-none, 1 -slight, 2-moderate, 3 -marked, 4-very marked), and the mean values were calculated. The cumulative PASI score was calculated at the end of the study.

[0175] Induration (Thickness): Comparative reduction of induration of psoriatic lesions in mice after treatment with formulation in Group C (GC -Plain Tapinarof) is not statistically significant while the reduction in Group F (Tapinarof + PEG + PLGA) enhanced formulation is statistically significant as compared to no treatment group B (GB). [Reference: Graph 1]

[0176] Erythema: In mice with psoriatic lesions, erythema decreased after treatment with plain Tapinarof (Group C, blue line). But greater reduction was observed in Group F (green line), which contained Tapinarof + PEG + PLGA, compared to the untreated control Group B (red line). [Reference: Graph 2]

[0177] Desquamation (Scaling): Comparative reduction in Scaling in psoriatic lesions in mice after treatment with plain Tapinarof in Group C (GC) which was not significant as compared to higher reduction in Group F (GF= Tapinarof+ PEG + PLGA) which was statistically significant as compared to no treatment in group B (GB). [Reference: Graph 3]

[0178] Cumulative PASI Score: Comparative reduction in Cumulative PASI Score in mice after treatment with plain Tapinarof in Group C (GC) which was not as significant as compared to highly significant reduction seen in Group F (GF= Tapinarof+ PEG + PLGA) as compared to no treatment in group B (GB)

[0179] {p<0.05 for Group C vs Group B and p<0.01 for Group F vs Group B}

[0180] [Reference Graph 4]Medrenova-202441087065

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[0182] Body weight

[0183] Individual body weights were recorded on the first day of dosing (before application) and twice a week thereafter (Day 1, 4, 7, 10, 14) followed by fasting body weight on the day of necropsy (Day 15). The percentage change in body weight was calculated at the end of the study.

[0184] Comparative reduction of body weight in mice after induction of psoriasis using Imiquimod and treated with formulation Group C (GC -Plain Tapinarof) vs Group F (Tapinarof + PEG + PLGA); enhanced formulation, on the background of no treatment group B (GB). As seen clearly, the increase in body weight in the enhanced formulation group F (GF) is higher than that for group C. The synergy of PEG & PLGA with Tapinarof is seen in terms of higher level of significance as compared to group C (Plain Tapinarof).

[0185] {p<0.01 for Group C vs Group B and p<0.001 for Group F vs Group B}

[0186] [Reference: Graph 5]

[0187] Conclusion

[0188] All intervention arms attenuated one or more disease indices, however their efficacy segregates into distinct tiers. Group F produced comparably greater mitigation, normalizing epidermal thickness, restoring body weight, and resulting in the highest decline in PASI scoring. Overall, based on the consistent grading of results across clinical, morphometric parameters, it was observed that Group F show maximum efficacy against IMQ-induced Psoriasis in mice.

[0189] Keratolytic Effect:

[0190] Since Tapinarof is not as good as other keratolytic agents (like Salicylic acid) in reducing hyperplasia of psoriatic lesions, enhancing this effect would cover for such a weakness. Our study demonstrated that Group F (epidermal thickness: average 25.33 pM) had much more keratolytic effect as compared to group C (epidermal thickness: average 42 pM) while normal animal skin that was included in group A showed average 23 pM thickness. As seen from the histopathological slides of Fig 1, our enhanced formulation almost normalized the skin thickness as compared to Tapinarof alone. This fact adds tremendous value to this formulation removing the handicap of plain Tapinarof in its inability to normalize skin thickness not being a strong keratolytic agent like Salicylates.

[0191] Anti-inflammatory effect:

[0192] As also seen from the histopathological slides in Fig 1, Tapinarof alone could not suppress inflammation induced by IMQ from the lower levels of Dermis where perifollicular inflammation persisted after treatment in group C. Whereas, in group F, there was no trace of any inflammation in the perifollicular area of dermis which our enhanced formulation could suppress and even in the upper papillary areas of dermis there were sparse signs of inflammation. Since Tapinarof’sMedrenova-202441087065

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[0194] approval has been on the grounds of being a non-steroidal anti-inflammatory agent, this feature enhancement is of extreme importance to its core effect.

Claims

Medrenova-20244108706517CLAIMS:

1. Atopical composition containing 0.5% to 3%w / w of Tapinarof, 10.00 % w / w - 70.00%w / w of Polyethylene Glycol (PEG) and 0.5% to l%w / w of polylactic-co-glycolic acid (PLGA).

2. Atopical composition as claimed in claim 1, wherein the PEG is selected from PEG-400, PEG-4000 or a mixture thereof.

3. A topical composition as claimed in any of the claims, wherein the composition is containing PEG in the below given range:a. PEG 400 in the concentration range of 10.00 % w / w - 70.00%w / w, more preferably in the range of 40.00 % w / w to 60.00% w / w, most preferred being 52.00- 57.00 % w / w.b. PEG 4000 is in the concentration range of 10.00 % w / w - 65.00%w / w, more preferably in the range of 20.00 % w / w to 45.00% w / w, most preferred being 25.00% w / w.

4. A topical composition as claimed in any of the claims 1 -3, which also contains 4-chlororesorcinol.

5. Atopical composition as claimed in any of the claims 1-3, which also contains propylene glycol.

6. A topical composition as claimed in any of the claims 1-3, which also contains sodium metabisulfite.

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