Patent Application
20210353594
The following relates to topical pharmaceutical compositions for the treatment of psoriasis and/or psoriatic arthritis.
Apremilast is a phosphodiesterase4 (PDE4) inhibitor. Apremilast is known chemically as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoin-dol-4-yl]acetamide, having chemical structure as given below:
Apremilast is at present available only as an oral formulation, marketed by Celgene Corp, under the trade name of OTEZLA®. OTEZLA® tablets are supplied in 10, 20, and 30 mg strengths for oral administration. OTEZLA® tablets are indicated (1) for the treatment of patients with active psoriatic arthritis and (2)for the treatment of patients with moderate to severe psoriasis who are candidates for phototherapy or systemic therapy.
Psoriasis is a chronic, non-contagious skin disorder that appears in many different forms and can affect any part of the body. The most common type of psoriasis is plaque psoriasis, occurring in 80% of people suffering from the disease. Plaque psoriasis is characterized by red patches and lesions that are covered by a build up of skin cells that are often called scales, and most commonly seen on the elbows, knees, scalp and back. Psoriasis is classified as mild, moderate, or severe, depending on the percentage of body surface involved and severity of the disease.
According to the National Institutes of Health, psoriasis is one of the most common human skin disorders, affecting greater than 3% of the United States population, or more than 5 million adults, of which greater than 1.5 million are considered to have a moderate to severe form of the disease. Although psoriasis is not fatal, it negatively impacts quality of life to a degree similar to heart disease and arthritis (Rapp et al. 1999). In addition, 10-30% of patients with psoriasis also develop a form of arthritis—psoriatic arthritis, which damages the bone and connective tissue around the joints. Furthermore, inflammatory mediators associated with psoriasis may increase the risk of obesity, diabetes, thrombosis, and atherosclerosis (Davidovici et al. 2010).
Though, apremilast is available as an effective oral therapy for psoriasis; an oral tablet composition is less suitable for patients who have difficulty in swallowing or whose gastro intestinal side effects are not reduced even after suggested oral dose titration. Thus, there is need for an effective pharmaceutical composition of apremilast suitable for topical administration that overcomes the problems associated with oral compositions.
An aspect relates to a safe and effective pharmaceutical composition comprising apremilast, suitable for topical administration.
Another aspect of embodiments of the present invention is to provide a topical pharmaceutical composition comprising apremilast, effective in the treatment of psoriasis.
Yet another aspect of embodiments of the present invention is to provide a simple method for preparation of a topical pharmaceutical composition comprising apremilast.
The inventors developed a novel composition designed for topical application comprising apremilast as the active ingredient, and surprisingly discovered that the composition effectually treated psoriasis without producing any of the negative side effects associated with oral administration as described in the prior art. Thus, the presently disclosed method provides a means of treating psoriasis that is cosmetically acceptable, effective, and easy to apply.
Thus, in one aspect embodiments of the present invention provide a pharmaceutical composition of apremilast suitable for topical administration having desired pharmacological activity and fewer side effects.
In another aspect, embodiments of the present invention are directed to a topical composition comprising a therapeutically effective amount of apremilast and a pharmaceutically acceptable topical carrier.
In yet another aspect, embodiments of the present invention are directed to methods of treating psoriasis by topical application to an affected epidermal area of a subject a topical dosage form comprising apremilast; and continuing the administration until symptoms of psoriasis are abated.
In another aspect, embodiments of the present invention set forth a safe and commercially viable process for preparation of a topical composition of apremilast that is sufficiently stable to provide an acceptable shelf life.
Some of the embodiments will be described in detail, with references to the following Figures, wherein like designations denote like members, wherein:
It has been surprisingly been found that pharmaceutical compositions of apremilast in the form of topical formulations provide desired pharmacological actions and fewer side effects.
Accordingly, embodiments of the present invention are directed to topical compositions comprising apremilast as the primary active agent and methods of use thereof for treating psoriasis. Specifically, the disclosed topical composition may be a cream, lotion, spray, oil, ointment, paste, dressing, solution, gel or other types of compositions that lends itself to topical application.
In one embodiment, the invention is directed to a topical composition for treating psoriasis comprising a therapeutically effective amount of apremilast and a pharmaceutically acceptable carrier.
A “therapeutically effective amount” is an amount necessary to palliate at least one symptom of psoriasis. For example, a therapeutically effective amount is sufficient to treat (i.e. alleviate or reduce) at least one of: itching/scratching, redness, inflammation, cracking, scaling, bleeding, etc. In an embodiment, the therapeutically effective amount of apremilast comprises between 0.5 to 15% by weight of the composition, for example 2 to 10%.
The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
The term “carrier” refers to a diluent, adjuvant, excipient, penetration enhancer, or vehicle with which an active ingredient is administered. Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin. In an embodiment, the pharmaceutically acceptable carrier comprises excipients commonly used in topically applied formulations (water, oil-based lotions, sprays, ointments, gels etc.).
As a non-limiting example, a pharmaceutically acceptable carrier may comprise water, glycerin, petrolatum, stearic acid, glycol stearate, dimethicone, isopropyl isostearate, tapioca starch, cetyl alcohol, glyceryl stearate, magnesium aluminum silicate, carbomer, ethylene brassylate, triethanolamine, disodium EDTA, phenoxyethanol, methyl paraben, propyl paraben, ethanol, bio-polymers (e.g., sodium hyaloronate), liposomes, nano- and micro-particulate carriers, and/or titanium dioxide. In an embodiment, the pharmaceutically acceptable carrier comprises dimethyl sulfoxide (DMSO), glycerol, propylene glycol, petrolatum water, and one or more pharmaceutically acceptable penetration enhancer (absorption promoter and/or accelerants).
In an embodiment, the pharmaceutical composition is in the form of topical gel or cream or ointment or solution or spray comprising apremilast and dimethyl sulfoxide (DMSO); in the ratio of 1:100 to100:1, for example 1:10 to 10:1, for example 1:1.
Typically, the topical compositions of the invention comprise skin penetration enhancers, pharmaceutical surfactants and solubility enhancers, oil phase components, aqueous phase components, emulsifiers, moisturizers, antioxidants, vitamins, lubricants, preservatives, stabilizers and other ingredients.
Skin penetration enhancers reversibly decrease the barrier resistance of the skin, which increases the amount of apremilast absorbed. In an embodiment, skin penetration enhancers include, but are not limited to, sulfoxides (e.g. DMSO), azones (e.g. laurocapram), pyrrolidones (e.g., 2-pyrrolidone), alcohols and alkanols (e.g., ethanol, decanol, etc.), oleic acid (and derivatives thereof), glycols (e.g., propylene glycol), dimethylformamide (DMF), dimethylacetamide (DMAC), fatty alcohols (e.g., lauryl alcohol), fatty acid esters, fatty acids, fatty alcohol ethers (e.g., EO-2-oleyl ether), terpenes, and biologics (e.g., lecithin).
Pharmaceutical surfactants or solubility enhancers include, but are not limited to, lauryl alcohol, polyoxyethylene ether, polyoxyethylene glycerol monostearate, stearic acid ester oxygen poly hydrocarbon, vitamin E succinate polyethylene glycol ester, sorbitan esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, organic esters (e.g. ethylene acetate), and poly hill dinitrate 80 (i.e. Tween 80 or its mixture). In an embodiment, the pharmaceutical surfactants or solubility enhancers include DMSO, polyvinylpyrrolidones, stearic acid hydrocarbon oxygen Poly (40) ester, lauryl alcohol polyoxyethylene (23) ether, vitamin E succinate polyethylene glycol ester, ethylene acetate, and polyoxyethylene (40) hydrogenated castor oil (and its mixtures, i.e. polyoxy (40) stearate). In a further embodiment the pharmaceutical surfactants or solubility enhancers include sodium lauryl sulphate and sorbitan esters.
Suitable oily phase may include, but are not limited to, glyceryl monoacetate, glycerol diacetate, glyceryl triacetate, stearic acid, soybean oil, corn oil, peanut oil, palmitic acid, palm oil, sunflower oil, olive oil, coconut oil, sesame oil, cotton seed oil, rapeseed oil, oleic acid, medium-chain triglycerides, single-decane triglyceride, animal fat (e.g., lanolin), mineral oils, paraffin, beeswax, petrolatum, hydrocarbons, vaseline, and mixtures thereof.
Aqueous phase components include, but are not limited to, de-ionized water, glycerol gelatin, cellulose derivatives (e.g., microcrystalline cellulose (Avicel PH 101)), and polyethylene glycol (PEG 300 to PEG 6000), and mixtures thereof.
Emulsifiers include, but are not limited to oleyl alcohol, polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30,glyceryl stearate, PEG-100 stearate, methyl myristate, isopropyl myristate, Arlacel 165, glyceryl stearate, PEG-100 stearate, steareth-2 and steareth-20, dimethicone copolyol, Polysorbate 20 (Tween 20), cetyl esters wax, Polysorbate 40 (Tween 40), Polysorbate 60 (Tween 60), Polysorbate 80 (Tween 80), lauramide DEA, cocamide
DEA, and cocamide MEA, Phospholipid PTC, alginate, carrageenan, Glucate DO, methylcellulose, polyvinyl alcohol, homopolymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol (Carbomer). In an embodiment, emulsifiers are selected from the group consisting of cetostearyl alcohol, stearic acid, magnesium stearate, sodium lauryl sulfate, triethanolamine, and magnesium aluminum silicate.
Moisturizers include, but are not limited to, glycerol, propylene glycol, and sorbitol.
Antioxidants include, but are not limited to, water soluble antioxidants, lipid-soluble antioxidants, vitamin C, vitamin C palmitate, propyl gallate, vitamin E (tocopherol), tert-butyl ether-hydroxybenzoate fennel, 2,6 di-tert-butyl-p-cresol, BHA, BHT, or mixtures of one or more antioxidants.
Lubricants include, but are not limited to, urea, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, and silica gel powder.
Preservatives include, but are not limited to, chloro-m-cresol, citric acid, disodium edetate, ethoxylated alcohol, glycerin, 1,2,6-hexanetriol, methylparaben, parabens, potassium, sorbate, propyl gallate, propylene glycol, propyl paraben, sodium bisulfate, sodium citrate, butyl paraben, sodium metabisulfite, chlorocresol, sorbic acid, tannic acid, zinc stearate, butylated hydroxytoluene, butylated hydroxyanisole, benzoic acid, salicylic acid, propyl paraben, dichlorobenzyl alcohol, formaldehyde, alpha-tocopherol, sodium ascorbate, ascorbic acid, ascorbyl palmitate phenol, m-cresol, bisphenol, cetrimide, benzalkonium chloride, sorbic acid, phenoxyethanol, and benzoyl peroxide. In an embodiment, preservatives are selected from the group consisting of hydroxylethyl benzene, hydroxylmethyl benzene, phenoxyethanol, chlorocresol, propyl paraben, and methyl paraben.
In an embodiment of the invention, topical composition of present invention has excipients that help adjusting the pH of the composition. Topical pharmaceutical compositions of the invention have a pH in the physiological range of 1 to 8, for example 2 to 7, for example 3 to 6.
Suitable pH adjusting agents include many pharmaceutically acceptable acids, bases and buffers. Suitable acids may include one or more of hydrochloric acid, phosphoric acid and lactic acid. Suitable bases may include one or more of diethanolamine, triethanolamine and sodium hydroxide. Suitable buffers may include phosphates, such as monobasic sodium phosphate, dibasic sodium phosphate, lactates and citrates.
Suitable stabilizers include, but are not limited to, chelating agents, stearyl alcohols.
The compositions of the present invention may further comprise excipients to provide better feel to the skin and lower irritation to the skin. The compositions may further contain additional excipients that enhance the aesthetic properties of the composition like coloring and flavoring agents.
In another aspect, embodiments of the present invention are directed to methods of treating psoriasis by topical application to an affected epidermal area of a subject a topical dosage form comprising apremilast; and continuing the administration until symptoms of psoriasis are abated.
Accordingly in another embodiment, the invention is directed to a method of treating psoriasis comprising the steps of topically applying a composition comprising apremilast within a pharmaceutically acceptable carrier to an affected epidermal area of a subject suffering from psoriasis. As used herein, “affected epidermal area” refers to those patches of skin that exhibit common indicators of psoriasis including inflammation, erythema, hyperproliferation, cracking, scaling, and bleeding.
Furthermore, the method is directed to treating a type of psoriasis selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, and erythrodermic psoriasis. In an embodiment, the method is directed to treating plaque psoriasis. Additionally, the subject suffering from psoriasis is an animal, preferably a mammal (e.g., pig, cow, horse, dog, cat, etc.), and most preferably the subject is a human.
In studies conducted thus far (see Example 8), no side effects have been observed. Thus, the methods disclosed herein represent a very desirable first- or second-line therapy for the treatment of psoriasis. Thus, in an embodiment, the method is directed to the treatment of mild, moderate, or severe psoriasis and may be directed to the treatment of moderate or severe psoriasis.
In another aspect, embodiments of the present invention set forth a safe and commercially viable process for preparation of a topical composition of apremilast that is sufficiently stable to provide an acceptable shelf life.
Thus, in another embodiment, the present invention is directed to methods of preparation of pharmaceutical compositions of apremilast, suitable for topical administration, and effective in the treatment of psoriasis. The compositions of the present invention may be prepared through any of the processes and techniques known in the art. The inventor have designed different formulation procedures, and varieties of excipients of oil and aqueous phases, surfactants and solubility enhancers, and emulsifiers in order to develop stable, uniform, and cosmetically acceptable compositions.
The principles, embodiments, and modes of operation of the present invention have been described in the foregoing specification. Embodiments of the invention which are intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The following examples further illustrate embodiments of the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.
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Animal:
The animal model used was Mice (BALB/c,) which were purchased from Mahaveer enterprises and all the experiments were approved by institutional ethical committee.
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Conclusion:
Although the invention has been illustrated and described in greater detail with reference to the preferred exemplary embodiments, the invention is not limited to the examples disclosed, and further variations can be inferred by a person skilled in the art, without departing from the scope of protection of the invention.
For the sake of clarity, it is to be understood that the use of “a” or “an” throughout this application does not exclude a plurality, and “comprising” does not exclude other steps or elements.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201641011015 | Mar 2016 | IN | national |
This application is a divisional application of U.S. application Ser. No. 16/088,801, filed Sep. 26, 2018, which claims priority to PCT Application No. PCT/IN2016/000237, having a filing date of Sep, 30, 2016, which is based upon and claims priority to IN Application No. 201641011015, having a filing date of Mar. 30, 2016, the entire contents of all priority documents which are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16088801 | Sep 2018 | US |
| Child | 17378758 | US |
