APREMILAST LOW-DOSE TOPICAL PHARMACEUTICAL COMPOSITIONS

Abstract

The present invention provides a low dose topical composition of Apremilast with pharmaceutically acceptable excipients. The present invention also relates to a topical clear gel composition of apremilast for delivering a desired therapeutic amount of drug to the site of action after topical application. The present invention also provides a process for preparation process for preparation of low dose apremilast topical composition with enhanced diffusion and dose-proportionate linear drug release from the composition.

Claims

1. A low dose clear topical composition of Apremilast comprising apremilast or its pharmaceutically acceptable salt in the range of 0.01-1.5% w/w with at least one solvent and one or more pharmaceutically acceptable excipient.

2. The topical composition as claimed in claim 1, wherein the said clear topical composition gives a linear and proportional drug release.

3. The topical composition as claimed in claim 1, wherein the said clear composition is a gel, paste, cream, ointment or lotion.

4. The topical composition as claimed in claim 1, wherein the said pharmaceutically acceptable excipient is selected from the group comprising of gelling agents, solvents, co-solvents, skin penetration enhancers, pharmaceutical surfactants, solubility enhancers or solubilizers, oil phase components, aqueous phase components, emulsifiers, moisturizers, antioxidants, vitamins, lubricants, preservatives, stabilizers, buffers, alkalizers or a mixture thereof.

5. The topical composition as claimed in claim 1, wherein the said pharmaceutical composition is suitable for topical application, comprising Apremilast or its pharmaceutically acceptable salt in lower amount capable of delivering therapeutically effective amounts in combination with pharmaceutically acceptable excipients for alleviating the symptoms of Psoriasis and associated inflammatory skin conditions.

6. The topical composition as claimed in claim 1, wherein the said composition characteristically provides enhanced drug delivery and skin permeation with minimal amount of Apremilast in the composition.

7. The topical composition as claimed in claim 1, wherein the said composition characteristically gives a proportionate increase in the amount of drug getting diffused across the diffusion layer, throughout the range of 0.01% to 1.5% apremilast w/w.

8. The topical composition as claimed in claim 1, wherein in the said composition the pharmaceutical excipient is a gelling agent and the ratio of Apremilast to gelling agent in the composition is 1:10 to 1:100.

9. The topical composition as claimed in claim 1, wherein the said pharmaceutically acceptable excipient is a penetration enhancer or solubilizer, wherein the solubilizer can be a single solubilizer or surfactant or a combination of solubilizer or surfactant.

10. A low dose topical composition of Apremilast with one or more pharmaceutically acceptable excipient with charactertic linear and dose proportionate enhanced diffusion, wherein the said composition is prepared by a process comprising of: a. Dispensing Apremilast, carrier or solvents, gelling agent, humectant, methyl paraben and propyl paraben; b. Weighing the required quantity of Apremilast and dissolving in required quantity of a suitable first solvent or carrier under stirring; wherein the stirring was continued until the complete solubilization of Apremilast; c. Weighing required quantity of water and a suitable humectant and mixing together under continuous stirring; d. Adding weighed quantity of a second solvent to the step c) mixture under stirring with continuous stirring for 10 min; e. Adding suitable gelling agent to the step d) mixture under stirring and the stirring was continued for 2 hrs till complete solubilization of the gelling agent; f. There after step b) drug solution was added to the step e) gel base under stirring; g. Separately weighed quantity of methyl and propyl parabens were then dissolved in required quantity of a third solvent. h. Then the step g) preservative solution was added to the step f) Apremilast gel under stirring, followed by continued stirring for 30 min; and i. Finally the pH of the gel was adjusted in the range of pH 6.0-7.0 by adding 10% w/v NaOH solution; wherein the solvent used in step a), b), d) and g) can be same or different solvents.

Description

BRIEF DESCRIPTION OF DRAWING

[0021] FIG. 1, shows cumulative drug release from Apremilast topical gel, wherein the drug release is linear with increased strength until drug is in solution form (clear gel) whereas the drug release is more or less constant in dispersive gels irrespective of strengths.

DETAILED DESCRIPTION

[0022] The inventors of the present invention are consistently working towards various approaches for developing compositions for better and effective remedy. In line with the ongoing research, the inventors have surprisingly found out that there is significant enhanced penetration of the drug or diffusion of the drug (Apremilast), when used in lower amounts i.e., the drug release is linear with increased strengths until drug is in solution (as in clear gels) form. Thus the inventors surprisingly found that at lower amounts of drug the topical composition has proportional increase in diffusion rate. However with gradual increase in the amount of drug the diffusion rate is almost constant and leads to a flat effect, this may be attributed to precipitation of the drug or Apremilast in the dispersive gels, or may be due to the saturation of the diffusion layer mimicking the skin.

[0023] The present disclosure is herein described in detail with reference to embodiments, which form a part here. Other embodiments may be used and/or other changes may be made without departing from the spirit or scope of the present disclosure. The illustrative embodiments described in the description are not meant to be limiting of the subject matter presented here.

[0024] The present invention pertains to topical composition of Apremilast containing lower amount of drug, various formulation were further evaluated with other components or excipients in order to obtain better acting and effective compositions.

[0025] The topical composition in the present invention is able to give proportionate increase in the amount of drug getting diffused across the diffusion layer, throughout the range of 0.01% to 1.5%.

[0026] In another embodiment the present invention relates to a lower amount of Apremilast in combination with is a plurality of excipients in specific quantity and combinations, for both solubilizing the active agent and forming a long acting, better penetrating consistent topical clear gel composition.

[0027] In another embodiment, the present invention provides a low dose topical gel or can be formulated as low dose topical cream, ointment, emulsion or lotion of Apremilast with at least one pharmaceutically acceptable excipient and having proportionate and enhanced skin diffusion/penetration, with better patient compliance, consistency and therapy.

[0028] In another embodiment, the present invention also provides a low dose topical composition of Apremilast with at least one pharmaceutically acceptable excipient and having linear and dose proportionate enhanced diffusion/penetration, with better patient compliance, consistency and therapy.

[0029] In yet another preferred embodiment the present invention provides a method of treating psoriasis or related inflammatory skin disorders such as dermatosis, eczema, rosacea, acne vulgaris, allergies, contact and atopic dermatitis, pruritus, seborrhoea, skin cancers, inflammation and others using a low dose composition of Apremilast in the range of 0.01 to 1.5% w/w of Apremilast.

[0030] In yet another embodiment the pharmaceutical compositions in the form of topical gels, creams, ointments, and lotions as prepared in the present invention provide desired pharmacological actions and fewer side effects, along with better patient compliance.

[0031] In yet another preferred embodiment the low dose topical composition of Apremilast in the present invention is able to provide an effective amount of drug at the site of action for treatment of mild to major psoriasis and is efficient in reducing the psoriatic scores in effective manner.

[0032] In one preferred embodiment of the invention, the Apremilast provided in the clear topical gel which is better than the dispersion gels, thereby comparatively giving a linear and proportionate diffusion of drug when compared with later.

[0033] In another embodiment of the invention, Apremilast is provided as a topical pharmaceutical composition with pharmaceutically acceptable carriers, solvents, solubilizers, humectants, penetration enhancers, surfactants, preservatives, gelling agents, co-solvents and other topically acceptable excipients.

[0034] In yet another embodiment of the invention, topical gel may comprise excipients that are hydrophilic and/or hydrophobic in nature.

[0035] In another preferred embodiment of the invention, the topical composition comprises of Apremilast or its pharmaceutically acceptable salt and a suitable solvent, solubilizer, a suitable carrier and penetration enhancer with gelling agent in suitable ratio, to give maximum average flux or diffusion of the drug through the skin layers.

[0036] Unless otherwise recited or required by the context, percent and “%” refer to percent by weight.

[0037] Topical pharmaceutical compositions of the invention include Apremilast in the concentration of 0.01% to 1.5% by weight, preferably 0.01 to 1% w/w, more preferably 0.05-0.5% w/w.

[0038] Topical pharmaceutical compositions of the invention include Apremilast and gelling agent in an amount of 0.01-1.5% w/w and 0.05-5% w/w respectively or in the ratio of 1:10 to 1:100 respectively.

[0039] Topical pharmaceutical compositions of the invention have a pH in the physiological range between 4 to 8 or 4.5 to 6.5.

[0040] In yet another preferred embodiment the ratio of drug to the solvent in the composition is ranging from 0.01:100 to 100:0.01 or 0.1:50 to 50:0.1 or 0.01:5 to 0.5:50.

[0041] In yet another preferred embodiment the ratio of drug to the co-solvent in the composition is ranging from 0.01:100 to 100:0.01 or 0.1:50 to 50:0.1 or 0.01:5 to 0.5:50.

[0042] In yet another embodiment the penetration enhancer or solubilizer in the composition can be a single solubilizer/surfactant or a combination of solubilizer/surfactants, combined in such a concentration to impart maximum drug diffusion through the skin.

[0043] In yet another embodiment the solvents used in the invention can have multiple application like a solvent can be used as co-solvent, penetration enhancer or solubilizer in the composition and can be a single solvent or a combination of solvent to play different roles as Solubilizers/penetration enhancer/surfactants/humectant, combined in such a concentration to impart maximum and linear drug diffusion through the skin.

[0044] In another preferred embodiment, the topical clear gel composition of the invention comprises Apremilast 0.01-1.5% w/w, gelling agent 0.05-5% w/w, solubilizer 1-30% w/w, penetration enhancer 5-40%, humectant 5-40%, solvent/carrier 2-20% w/w, preservative 0.05-5% w/w, purified water 5-80% w/w and suitable pH adjusting agent or buffering agent or alkalizer.

[0045] In another preferred embodiment, the topical clear gel composition of the invention comprises Apremilast 0.01-0.5% w/w, gelling agent 0.05-5% w/w, solubilizer 1-30% w/w, penetration enhancer 5-40%, humectant 5-40%, solvent/carrier 2-20% w/w, preservative 0.05-5% w/w, purified water 5-80% w/w and suitable pH adjusting agent or buffering agent or alkalizer.

[0046] In another preferred embodiment, the topical clear gel composition of the invention comprises Apremilast 0.01-1.5% w/w, gelling agent 0.05-5% w/w, a first solvent 1-30% w/w, a second solvent 5-40% w/w, a humectant 5-40% w/w, a third solvent 2-20% w/w, preservative 0.05-5% w/w, purified water 5-80% w/w and suitable pH adjusting agent or buffering agent or alkalizer.

[0047] In another preferred embodiment, the topical clear gel composition of the invention comprises Apremilast 0.01-0.5% w/w, gelling agent 0.05-5% w/w, a first solvent 1-30% w/w, a second solvent 5-40% w/w, a humectant 5-40% w/w, a third solvent 2-20% w/w, preservative 0.05-5% w/w, purified water 5-80% w/w and suitable pH adjusting agent or buffering agent or alkalizer.

[0048] In yet another embodiment the first, second and third solvent used in the present invention compositions can be used interchangeably in different ratios to provide various formulations with similar or varying release profiles.

[0049] In yet another embodiment of the invention, topical clear gel composition also comprises excipients to provide better feel to the skin, no greasiness or feel of any gritty particles and lower irritation to the skin.

[0050] In one of the embodiment of the invention, topical pharmaceutical composition may optionally comprise of suitable preservative or fragrance.

[0051] In one preferred embodiment, the invention is directed to a topical composition for treating psoriasis comprising a therapeutically effective amount of Apremilast, a suitable solvent or mixture thereof, a solubilizer/permeation enhancer and a pharmaceutically acceptable carrier.

[0052] In yet another preferred embodiment the process for preparation of topical clear gel composition of the invention comprises of: [0053] a) Dispensing actual quantities of Apremilast, carrier/solvent, gelling agent, 2.sup.nd solvent, humectant, methyl paraben, propyl paraben and 3.sup.rd solvent. [0054] b) Weighing the required quantity of Apremilast and dissolving in required quantity of suitable solvent/carrier (1.sup.st solvent) under stirring. The stirring was continued until the complete solubilization of Apremilast. [0055] c) Weighing required quantity of water and a suitable humectant and mixing together under continuous stirring. [0056] d) Adding weighed quantity of 2.sup.nd solvent to the step c) mixture under stirring with continuous stirring for 10 min. [0057] e) Then suitable gelling agent was added to the step d) mixture under stirring and the stirring was continued for 2 hrs till complete solubilization of the gelling agent. [0058] f) There after step b) drug solution was added to the step e) gel base under stirring. [0059] g) Separately weighed quantity of methyl and propyl parabens were then dissolved in required quantity of 3.sup.rd solvent. [0060] h) Then the step g) preservative solution was added to the step f) Apremilast gel under stirring. Followed by continued stirring for 30 min. [0061] i) Finally the pH of the gel was adjusted in the range of pH 6.0-7.0 by adding 10% w/v NaOH solution.

[0062] In the process the solvents used in step a), b), d) and g) can be same or different and can play a similar or distinct role in the topical formulation.

[0063] A “therapeutically effective amount” is an amount necessary to palliate or treat 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. Preferably, the therapeutically effective amount of Apremilast comprises between 0.01 to 1.5% by weight of the composition, more preferably 0.05 to 0.5% w/w of the composition.

[0064] In an embodiment of the invention, topical composition of present invention has excipients that help effective diffusion/penetration of Apremilast in to the skin and provide ease of application, spreadability and cleaning.

[0065] Non-Limiting Lists of the Excipients that can be Used in the Composition are:

[0066] Typically, the topical compositions of the invention comprise various gelling agents, solvents and co-solvents, skin penetration enhancers, pharmaceutical surfactants and solubility enhancers, oil phase components, aqueous phase components, emulsifiers, moisturizers, antioxidants, vitamins, lubricants, preservatives, stabilizers, buffers, alkalizers and other ingredients. Also the components/excipients/solvents as embodied in the present composition may have more than one application.

[0067] Various gelling agents include gelling agents from synthetic and other sources, carbopol and its derivatives and any other pharmaceutically acceptable gelling agents, further gelling agents include, but are not limited to gums, acrylic acid and acrylate polymers and. copolymers, and cellulose derivatives (e.g., hydroxymethyl cellulose and hydroxypropyl cellulose), one high molecular weight, cross linked polyacrylic acid polymer, Carbopol 10 NF. Pharmaceutically acceptable water-gelling agents preferably are carbomers, glyceryl polyacrylates, and combinations thereof. Various viscosity grades sold under the trademark designation CARBOPOL® by B.F. Goodrich Company, Cleveland, Ohio. Particularly preferred is CARBOPOL® 980. Glyceryl polyacrylates are esters of glycerine and polyacrylic acid available in various viscosity grades sold as an aqueous jelly under the trademark designation, HISPAGEL, by Hispano Quimica S. A., Barcelona, Spain.

[0068] Skin penetration enhancers reversibly decrease the barrier resistance of the skin, which increases the amount of Apremilast absorbed. Preferably, skin penetration enhancers include, but are not limited to, PGs (Propylene Glycols), 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 lecithin.

[0069] 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 a preferred 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). Still, in a more preferred embodiment the pharmaceutical surfactants or solubility enhancers include sodium lauryl sulphate and sorbitan esters.

[0070] Suitable oily phase may include, but are not limited to, glyceryl monoacetate, glycerol diacetate, glyceryl triacetate, stearic acid, various commercially available pharmaceutical grade oils, oleic acid, medium-chain triglycerides, single-decane triglyceride, fat (e.g., lanolin), mineral oils, paraffin, waxes, petrolatum, hydrocarbons, vaseline, and mixtures thereof.

[0071] Preferred non-limiting examples of hydrophobic excipients useful in the present composition include small and medium chain triglycerides, petrolatum, red petrolatum, white petrolatum, liquid petrolatum, semi-solid petrolatum, light mineral oil, heavy mineral oil, white mineral oil, mineral oil alcohols, C.sub.7-C.sub.40 branched chain hydrocarbons, C.sub.10-C.sub.30 alcohol esters of C.sub.10-C.sub.30 carboxylic acids, C.sub.10-C.sub.30 alcohol esters of C.sub.10-C.sub.30 dicarboxylic acids, monoglycerides of C.sub.10-C.sub.30 carboxylic acids, diglycerides of C.sub.10-C.sub.30 carboxylic acids, triglycerides of C.sub.10-C.sub.30 carboxylic acids, ethylene glycol monoesters of C.sub.10-C.sub.30 carboxylic acids, ethylene glycol diesters of C.sub.10-C.sub.30 carboxylic acids, propylene glycol monoesters of C.sub.10-C.sub.30 carboxylic acids, propylene glycol diesters of C.sub.10-C.sub.30 carboxylic acids, C.sub.10-C.sub.30 carboxylic acid monesters and polyesters of sugars, pharmaceutical grade oils and their hydrogenated oil forms, Shea butter, polypropylene glycols, polypropylene glycol C.sub.4-C.sub.20 alkyl ethers, di C.sub.8-C.sub.30 alkyl ethers, synthetic hydrocarbons, derivatives thereof, and mixtures thereof. Also additionally preferred, non-limiting examples of other hydrophobic agents include ethylene glycol distearate, cetyl palmitate, myristyl myristate, stearyl stearate, cetyl stearate, behenyl behenate, caprylic/capric triglyceride, PEG-6 caprylic/capric triglyceride, PEG-8 caprylic/capric triglyceride, derivatives thereof, and mixtures thereof.

[0072] Further the composition may comprise pharmaceutically acceptable carriers like water, glycerin, petrolatum, stearic acid, glycol stearate, dimethicone, isopropyl isostearate, pharmaceutical grade 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. More preferably, 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). 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.

[0073] Emulsifiers include, but are not limited to Emulcire 61 WL 1349, Gelot 64, 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, Carbopol and Carbomer. Preferably, emulsifiers are selected from the group consisting of cetostearyl alcohol, stearic acid, magnesium stearate, sodium lauryl sulfate, triethanolamine, and magnesium aluminum silicate.

[0074] Any other emulsifiers known to those of skill in the art as useful in the formation of topical compositions are further contemplated herein.

[0075] Moisturizers include, but are not limited to, glycerol, pentylene glycol, butylene glycol, polyethylene glycol, sodium pyrrolidone carboxylate, alpha-hydroxy acids, beta-hydroxy acids, polyhydric alcohols, ethoxylated and propoxylated polyols, polyols, polysaccharides, panthenol, hexylene glycol, propylene glycol, dipropylene glycol, sorbitol, derivatives thereof, and mixtures thereof.

[0076] 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.

[0077] Lubricants include, but are not limited to, urea, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, and silica gel powder.

[0078] 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. Preferably, preservatives are selected from the group consisting of hydroxylethyl benzene, hydroxylmethyl benzene, phenoxyethanol, chlorocresol, propyl paraben, and methyl paraben.

[0079] Any other solvent/co-solvent known to those of skill in the art as useful in the formation of topical compositions are further contemplated herein. Further the solvent and co-solvent can have multiple applications like Solubilizers, penetration enhancers, humectants, moisturisers and other topically feasible roles known to a person skilled in the art.

[0080] The presently preferred compositions may further contain a pH modifier. Preferably, the presently preferred compositions can comprise about 0.01% to about 10% by weight of a pH modifier. Preferred non-limiting examples of neutralizing pH modifiers that can optionally be included in these compositions include inorganic hydroxides, inorganic oxides, inorganic salts of weak acids, derivatives thereof, and mixtures thereof.

[0081] Preferred non-limiting examples of inorganic hydroxides useful in this regard include ammonium hydroxide, alkali metal hydroxide, alkaline earth metal hydroxides, derivatives thereof, and mixtures thereof.

[0082] Preferred inorganic hydroxides useful in this regard include ammonium hydroxide, monovalent alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, divalent alkali earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, derivatives thereof, and mixtures thereof.

[0083] Preferred non-limiting examples of inorganic oxides useful in this regard include magnesium oxide, calcium oxide, derivatives thereof, and mixtures thereof.

[0084] Preferred, non-limiting examples of inorganic salts of weak acids useful in this regard include ammonium phosphate (dibasic), alkali metal salts of weak acids such as sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate (tribasic), sodium phosphate (dibasic), potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate (dibasic), potassium phosphate (tribasic), alkaline earth metal salts of weak acids such as magnesium phosphate and calcium phosphate, derivatives thereof, and mixtures thereof.

[0085] In an embodiment of the invention, topical composition of present invention has pH adjusting agents that help in adjusting the pH of the composition between pH of about 4.5 to about 7.5 to provide a stable and non-irritating composition. Such 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, triethylamine and sodium hydroxide. Suitable buffers may include phosphates, such as monobasic sodium phosphate, dibasic sodium phosphate, lactates and citrates.

Definitions

[0086] As used here, the following terms have the following definitions:

[0087] “Active Pharmaceutical Ingredients (APIs)” refer to chemical compounds that induce a desired effect, and include agents that are therapeutically or prophylactically effective.

[0088] “Permeation enhancement” refers to an increase in the permeability of the skin or mucosal tissue to the selected active pharmaceutical ingredients.

[0089] “Topical administration” refers to delivery of a topical drug or active pharmaceutical ingredient to the skin or mucosa, thus providing a local effect.

[0090] “Treating” or “Treatment” refers to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.

[0091] 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.

[0092] The term “penetration enhancer” refers to vehicle, carrier, diluent, adjuvant, excipient, or solubilizer with which an active ingredient is administered. Such pharmaceutical agents can be lipophilic or hydrophobic components.

[0093] The term “carrier” refers to a diluent, adjuvant, excipient, penetration enhancer, or vehicle with which an active ingredient is administered.

EXAMPLES

[0094] The following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the present invention only and are presented in the cause of proving what is believed to be the most useful and readily understood description of formulation procedures as well as of the principles and conceptual aspects of the invention. It will be evident to those skilled in the art that the invention is not limited to the details of the following illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Example 1: Apremilast Topical Clear Gel

[0095]

TABLE-US-00001 Component % w/w Apremilast 0.01-1.5 DMSO   1-30 Carbopol 0.05-5   Glycerin   5-40 Propylene glycol   5-40 Ethanol   2-20 Methyl paraben 0.05-5   propyl paraben 0.05-5   Purified Water   5-80 Sodium hydroxide q.s. Total 100

[0096] Brief Manufacturing Process: [0097] a) Actual quantities of Apremilast, DMSO, carbopol, glycerine, propylene glycol, methyl paraben, propyl paraben and ethanol were dispensed. [0098] b) The Apremilast was weighed and dissolved in required quantity of DMSO under stirring. The stirring was continued until the complete solubilization of Apremilast. [0099] c) Weighed quantity of water and propylene glycol were mixed together under continuous stirring. [0100] d) Followed by adding weighed quantity of glycerine to the step c) mixture under stirring with continuous stirring for 10 min. [0101] e) Then carbopol was added to the step d) mixture under stirring and the stirring was continued for 2 hrs till complete solubilization of carbopol. [0102] f) There after step b) drug solution was added to the step e) gel base under stirring. [0103] g) Separately weighed quantity of methyl and propyl parabens were then dissolved in required quantity of ethanol. [0104] h) Then the step g) preservative solution was added to the step f) Apremilast gel under stirring. Followed by continued stirring for 30 min. [0105] i) Finally the pH of the gel was adjusted to 6.0±0.5 by adding 10% w/v NaOH solution.

Example 2: Apremilast Topical Clear Gels

[0106]

TABLE-US-00002 0.05% w/w 0.10% w/w 0.25% w/w Components gel (w/w) gel (% w/w) gel (% w/w) Apremilast 0.05 0.10 0.25 DMSO q.s q.s q.s Carbopol 10NF 0.5  0.5  0.5  Glycerin q.s q.s q.s Propylene glycol 29.3   29.3   29.3   Ethanol USP q.s q.s q.s Methyl paraben 0.2  0.2  0.2  Propyl paraben 0.2  0.2  0.2  Purified Water 29.4   29.4   29.2   Total 100      100      100     

Example 3: Apremilast Dispersive Gels

[0107]

TABLE-US-00003 0.75% w/w 1% w/w 2% w/w gel 4% w/w gel Components gel (% w/w) gel (% w/w) (% w/w) (% w/w) Apremilast 0.75 1 2 4 DMSO q.s q.s q.s q.s Carbopol 10NF 0.5   0.5  0.5  0.5 Glycerin q.s q.s q.s q.s Propylene 29.3   29.3 29.3 29.3 glycol Ethanol USP q.s q.s q.s q.s Methyl paraben 0.2   0.2  0.2  0.2 Propyl paraben 0.2   0.2  0.2  0.2 Purified Water 28.7   28.5 27.5 25.5 Total 100      100    100    100   

[0108] Observation:

[0109] The gels prepared in Examples 2 and 3 as per procedure given in Example 1 above, were further evaluated for various physical parameter and in vitro drug release of gels over a period of 48 hours as given in Table 1 (with respect to Example 2 for clear gel) and Table 2 (with respect to Example 3 for dispersive gel). The observation study depicted following results as tabulated below:

TABLE-US-00004 TABLE 1 For composition of Apremilast in lower amount - clear gel - Example 2 Strength 0.05% 0.10% 0.25% 1 g gel contains 500 μg API 1000 μg API 2500 μg API Physical Clear gel Clear gel Clear gel observation Physical properties Clear transparent Clear transparent Clear transparent Description viscous gel viscous gel viscous gel pH (10% 6.03 6.09 6.09 solution) Viscosity (cps) 2138 2184 1997 Time (Hrs) Cumulative drug release (μg/20 ml)  0 0.0 0.0 0.0  2 0.0 0.3 2.2  4 0.2 1.2 7.3  6 1.7 4.1 15.2  8 3.5 7.1 22.7 12 6.8 13.2 42.8 24 15.5 27.8 74.7 30 19.2 34.7 94.6 48 24.0 43.6 113.9

TABLE-US-00005 TABLE 2 For composition of Apremilast - Dispersive Gel - Example 3 Strength 0.75% 1% 2% 4% 1 g gel contains 7500 μg API 10000 μg API 20000 μg API 40000 μg API Physical observation API dispersed API dispersed API dispersed API dispersed Physical properties Description White is off white White to off white White to off white White to off white viscous gel viscous gel viscous gel viscous gel pH (10% solution) 6.08 6.09 6.07 6.02 Viscosity (cps) 1959 1913 1725 1875 Time (Hrs) Cumulative drug release (μg/20 ml)  0 0.0 0.0 0.0 0.0  2 0.0 1.6 1.8 3.3  4 10.1 13.9 13.6 16.2  6 24.6 28.7 25.1 29.0  8 39.3 45.8 42.7 46.1 12 79.7 88.6 80.3 80.9 24 148.7 190.0 171.3 162.0 30 191.7 236.0 208.4 189.0 48 247.7 296.4 277.5 237.4

[0110] Based on the above Table 1 and Table 2 it was inferred that the drug release is linear with increased strength until the drug is in solution form as in Example 2 clear gels, whereas in case of Example 3 dispersive gels the drug release is more or less constant irrespective of strengths. Thus the present invention clear gels were found to be effective in providing a linear release of drug over a period of 48 hours even with a lesser amount of drug, however the higher amount of drug containing dispersive gels were found to be unclear or opaque due to the possible precipitation of the drug or presence of drug in dispersion forms in the formulation over time, thereby the drug release was flat or constant irrespective of a higher strength (as shown in FIG. 1).

[0111] The Drug samples were further evaluated in terms of other physical and biological parameters and where found to be satisfactory over conventional dosage forms and high strength compositions of Apremilast.