JP7850667B2 - Roflumilast topical formulation with improved delivery and plasma half-life - Google Patents

Description

This application is a continuation-in-part application of U.S. serial number 16/136,804 filed on September 20, 2018, a continuation-in-part application of U.S. serial number 15/848,505 filed on December 20, 2017 (currently U.S. Patent No. 10,105,354 issued on October 23, 2018), a continuation-in-part application of U.S. serial number 15/676,356 filed on August 14, 2017 (U.S. Patent No. 9,884,050 issued on February 6, 2018), and a divisional application of U.S. serial number 15/616,409 filed on June 7, 2017 (U.S. Patent No. 9,895,359 issued on February 20, 2018), the disclosures of which are incorporated herein by reference.

This invention relates to a method for improving the efflux kinetics of topically administered roflumilast. More specifically, the invention relates to a pharmaceutically acceptable emulsion, suspension, gel, foam, or solution formulated to have improved delivery and a longer half-life after topical administration.

Increased adherence to appropriately prescribed medical treatments is associated with better therapeutic outcomes. This pharmacological self-evident fact has been the subject of intensive research and quantification since the introduction of antiretroviral (ART) therapy for HIV treatment. Determining factors that negatively impact adherence to ART therapy (Schaecher 2013) was crucial for both patient care (reducing morbidity and mortality) and maintaining viral suppression (key to reducing the risk of HIV transmission). Two factors strongly influenced adherence to ART treatment were: 1) difficulty in complying with prescribed treatments, and 2) the occurrence of treatment-related side effects, particularly gastrointestinal adverse events. Adherence to treatments in patients with chronic skin disorders such as psoriasis, though with fewer public health concerns, has also been studied (Kircik, 2008). Similar to ART therapy, adherence to psoriasis treatment is negatively affected if the prescribed treatment interferes with daily routines or requires more frequent administration than once daily, making it difficult to follow. Regarding topical treatment for psoriasis, the adherence rate for once-daily dosing regimens was 82%, compared to only 44% for twice-daily dosing regimens (Zaghloul, 2004). For chronic skin diseases, adherence to treatment decreases with longer treatment durations (Rosenstock, 1985). This means that significant improvement in psoriatic plaques (defined as a reduction in size, thickness, or inflammation) within the first week of topical application improves treatment adherence compared to therapies requiring three or four weeks before significant disease clearance.

Adherence to treatment is the level of consistency between the patient's actual treatment plan and the prescribed treatment plan during the initiation and discontinuation of topical therapy. In patients with psoriasis, discontinuation of therapy occurs when plaques have completely or nearly disappeared, or when the therapy is abandoned due to adverse events or lack of efficacy. Failure to follow prescribed treatment is called poor adherence. Poor adherence most often manifests as random missed doses, which can be non-consecutive or two consecutive missed doses by chance. Three or more consecutive missed doses may be defined as a drug-free day to indicate this most serious form of poor adherence. When a patient asks, “What happens if I miss a dose?”, that question is called a patient concern regarding poor adherence. One of the more common concerns for people receiving a once-daily treatment plan compared to two or four-times-daily dosing is poor adherence.

The susceptibility of therapeutic success to incomplete adherence is driven by a property known as “tolerance” (Urquhart, 1997). A tolerant drug is one whose therapeutic outcomes are robust to a common pattern of incomplete adherence. Tolerance is a function of the duration of action of the active pharmaceutical ingredient (API) administered from a particular formulation and the dosing interval of the drug product. A drug is considered tolerant if its duration of action significantly exceeds the dosing interval. The tolerance index is the number of consecutive missed doses that may occur with minimal loss of drug effect. The duration of drug effect relates to the pharmacokinetic (PK) and pharmacodynamic (PD) properties inherent to the drug substance, as well as the exogenous PK properties of the drug delivery system.

One factor determining the duration of drug action is the plasma half-life. The plasma concentration of a drug halves after one half-life. In each subsequent half-life, the plasma concentration decreases, and therefore less drug is excreted. Thus, after one half-life, 50% of the absorbed drug remains in the body; after two half-lives, 25% remains; and after four half-lives, 6.25% remains, which is unlikely to have a significant therapeutic effect. The drug's half-life is important in determining the appropriate dosing interval. A small improvement in half-life for drugs with short half-lives can significantly reduce the dose administered. Short half-lives result in a high peak-to-trough ratio, requiring more frequent dosing. More frequent dosing can result in poor patient outcomes due to decreased patient compliance (incomplete adherence).

Roflumilast is known to be suitable as a bronchotherapy agent and for the treatment of inflammatory disorders. Compositions containing roflumilast have been used in human and veterinary medicine and have been proposed for the treatment and prevention of diseases including, but not limited to, inflammatory and allergen-induced airway disorders (e.g., bronchitis, asthma, COPD); skin diseases (e.g., proliferative, inflammatory, and allergen-induced skin disorders); and generalized inflammation in the gastrointestinal region (Crohn's disease and ulcerative colitis).

Roflumilast and its synthesis are described in U.S. Patent No. 5,712,298 ("Patent No. 298"), which is incorporated herein by reference. ^* ( ^* Unless otherwise indicated, references incorporated herein by reference are incorporated herein by reference as they are.) It has long been recognized that pharmaceutical compounds having phosphodiesterase (PDE) inhibitory properties, such as roflumilast, are useful for treating psoriasis and atopic dermatitis (Patent No. 298, column 11 (col), lines 52-61) and other chronic inflammatory and allergen-induced skin diseases. For the treatment of such skin diseases, roflumilast emulsions, suspensions, gels or solutions for topical application are described (Patent No. 298, column 12, lines 37-64). Although oral tablets of roflumilast are commercially available, the low water solubility of the compound is reported in International Publication No. 95/01338 (corresponding to Patent No. 298, incorporated herein by reference) to be only 0.53 mg/l at 21°C. This low water solubility has been a problem with the development of parenteral formulations and topical emulsions, suspensions, gels, or solutions containing water. In U.S. Patent No. 9,205,044 (incorporated herein by reference), the insufficient water solubility of roflumilast was overcome by using alkoxylated fats, particularly polyoxyethylated 12-hydroxystearic acid, as a cosolvent for parenteral administration. In European Patent No. 1511516B1 (corresponding to U.S. Patent Application Publication No. 14/075,035, incorporated herein by reference), the low water solubility of roflumilast was overcome by compounding it with polyethylene glycol 400 (PEG 400) at a concentration exceeding 62% (w/w) while maintaining the water weight percentage below 10% in a topical emulsion (cream) formulation.

Topical application of potent pharmacological agents like roflumilast has been found to offer superior delivery, lower systemic exposure, and greater ease of use for patients. The molecular structure of a compound ultimately determines the drug's ability to penetrate the epithelium of the tissue to which the product is applied. With regard to topical application to the skin, the selection of components of the formulation determines the maximum skin penetration that the formulationer can achieve. Creams, lotions, gels, ointments, and foams are just a few of the better-known forms of topical products containing active pharmaceutical ingredients (APIs) for skin application. To ensure consistent delivery of APIs into or across the skin, it must either: 1) remain dissolved throughout the shelf life of the topical product, or 2) remain suspended as particles with an unchanging crystal habit and unchanging particle size distribution throughout the shelf life of the topical product.

The ability of a dissolved active ingredient to penetrate the skin barrier is determined by its molecular structure. A well-known relationship between molecular structure and skin penetration is that increasing molecular weight decreases the rate at which the active ingredient crosses the skin (JD Bos, MM Meinardi, Exp Dermatol. 2000 Jun;9(3):165-9). Another well-understood relationship is that increasing the octanol-water partition coefficient of a hydrophilic active ingredient initially increases the rate at which the active ingredient penetrates the skin, but then decreases skin penetration once the active ingredient becomes too lipophilic to leave the stratum corneum and distribute into the lower layers of the epidermis (DW Osborne and WJ Lambert, Prodrugs for Dermal Delivery, KB Sloane ed., Marcel Dekker, New York 163-178 (1992)). The optimal octanol-water partition coefficient is usually at a log P value of 2–3. The rate at which the active ingredient crosses into the viable epidermis can be further modified based on the composition of the topical product. Since dissolved ionized active ingredients typically do not penetrate the skin as effectively as non-charged active ingredients, the final pH of the formulation can be important (N. Li, X. Wu, W. Jia, MC Zhang, F. Tan, and J Zhang. Drug Dev Indust Pharm 38(8)985-994). Functional ingredients, such as skin penetration enhancers (DW Osborne and JJ Henke, Pharmaceutical Technology 21 (11)58-66(1997)), can be added to topical products to increase skin penetration. With respect to dissolved active substances in topical formulations, the closer the drug concentration is to the amount of active substance required to saturate the drug product, the greater the thermodynamic driving force for the active substance across the skin, i.e., the greater the skin flux of the active substance. Scientific literature guides formulations regarding how much penetration through polar, nonpolar, and intercellular lipid pathways, or transfollicular penetration, should be increased. While these theories and mechanisms are sometimes contradictory, it is generally accepted that the most consistent skin penetration of drugs from topical products occurs when the active ingredient is dissolved in the formulation. For this reason, formulations generally avoid developing topical products in which particles or crystals of the active ingredient will precipitate during storage, following the storage instructions indicated on the label. Precipitation of the active ingredient can occur for a variety of reasons. Certain active ingredients may tend to form supersaturated solutions when formulated with certain pharmaceutically acceptable excipients. At the time of manufacture, all of the active ingredient will be in solution. After days, weeks, or months, this metastable topical product will equilibrate, and particles of the active ingredient will form. If the topical product contains a volatile solvent such as ethanol, evaporation of the solvent during storage may result in precipitation of the active ingredient. Possibly less soluble polymorphs (Pudipeddi and Serajuddin, J. Pharm. Sci., 94 (5) 929-939 (2005)) may form active ingredient particles that act as nuclei in topical products and will not redissolve. Other products may be formulated too close to the saturation limit of the active ingredient, which means that even slight changes in storage temperature will cause precipitation. It should be noted that dramatic temperature changes that may occur during transport are expected to cause reversible precipitation of the active ingredient. Regardless of the reason, irreversible precipitation of the active ingredient during storage of topical products can have a significant impact on the bioavailability and efficacy of the product, as only dissolved active ingredients can penetrate into the intact stratum corneum, the outermost layer of the skin's epithelium.

With respect to suspended active ingredients, properties other than molecular structure influence skin penetration. The ratio of dissolved active ingredient to suspended active ingredient can have a significant effect on the amount of active substance delivered after topical application. It has been shown that optimal drug delivery can be achieved with respect to specific drugs and diseases by utilizing topical compositions containing dissolved active ingredients, which have the ability to penetrate the stratum corneum of the epidermis and become systemically available, together with active ingredients in the form of particulate matter that do not readily cross the stratum corneum of the epidermis (U.S. Patent No. 5,863,560, incorporated herein by reference). Another property of suspended active ingredients that influences their delivery is the distribution of the size of the suspended particles. It has been shown that 6-micron particles will target hair follicles and penetrate to a depth of 500 micrometers in the terminal hair. For suspended particles ranging in size from 0.75 microns to 1.5 microns, the particles penetrate the hair terminals to a depth of 800 micrometers (A Patzelt, F Knorr, U Blume-Peytavi, W Sterry, J Lademann, Drug Discovery Today: Disease Mechanisms, 5(2)2008 pages e173-e181). Therefore, with respect to suspended active ingredients, skin permeability depends on the following properties: 1) the molecular structure of the dissolved active ingredient, 2) the particle/crystal structure of the suspended active ingredient, 3) the particle size of the suspended active ingredient, and 4) the particle size distribution of the suspended active ingredient. The ability of topical product compositions to modify skin permeability is similar for suspended and dissolved active ingredients. Because skin permeability depends on further properties of the suspended active ingredient, consistent delivery from topical products containing suspended active ingredients is more difficult to maintain than for topical products containing only dissolved active ingredients.

Consistent delivery of suspended active ingredients from topical products is ensured by formulation in the product such that the suspended particles do not change significantly in size or quantity over the product's shelf life. Changes over time in the ratio of dissolved active ingredients to particulate active ingredients can dramatically alter the skin penetration of the active ingredients. The same mechanisms described above that can cause precipitation of dissolved active ingredients (supersaturation, temperature changes, evaporation, polymorphic transitions) can alter the dissolve-to-particle ratio for suspended active ingredients. Changes over time in the particle size or particle size distribution of dispersed active ingredients can also dramatically alter the skin penetration of the active ingredients. Sometimes, this change in particle size or particle size distribution can be explained by Ostwald maturation of particles. Ostwald maturation occurs when smaller particles in a topical product dissolve and reprecipitation onto larger particles suspended in the same container of the topical product. Over time, this phenomenon shifts the particle size distribution toward larger particles at the expense of smaller particles. The Ostwald aging and precipitation of less soluble polymorphs represent two major challenges in the development of topical products containing suspended active ingredients.

In addition to consistent delivery of the suspended active ingredient from topical products, the success of treatment also depends on the elimination kinetics of the active ingredient. After the drug is absorbed into the patient's body, elimination begins, thereby decreasing the concentration over time. The half-life determines how long the drug will remain effective. When multiple doses of 0.375 mg of immediate-release oral roflumilast (Huang, 2018) were administered, the mean plasma half-life of the drug was found to be approximately 1 day (the mean for 12 subjects was 25.6 hours, with a standard deviation of 8.5 hours). Since the peak plasma concentration (11.4 ng of roflumilast per 1 mL of plasma) occurs approximately 1 hour after oral administration of roflumilast, the mean plasma concentration at the time of the first missed dose (1 day after the most recent dose) would be approximately 5.7 ng/mL (half of the peak plasma concentration of 11.4 ng/mL). If two consecutive doses are missed, the plasma concentration of roflumilast is estimated to be approximately 2.8 ng/mL two days after the most recent dose and approximately 1.4 ng/mL just before returning to adherence to the treatment. That is, the patient will not miss three consecutive doses and will take the tablet 72 hours after the most recent oral dose of roflumilast. If the half-life of roflumilast can be increased, and as a result the systemic plasma level of roflumilast does not decrease by half each day of missed doses, the tolerance index for the drug delivery system will increase. Regarding oral roflumilast, the use of a sustained-release oral drug delivery system instead of an immediate-release tablet, as studied by Huang, may be an example of exogenous PK property modification to increase tolerance for product adherence failure, which would benefit patients who miss one or more doses of roflumilast.

U.S. Patent No. 5,712,298 International Publication No. 95/01338 U.S. Patent No. 9,205,044 European Patent No. 1511516B1 U.S. Patent Application Publication No. 14/075,035

Schaecher 2013 Kircik, 2008 Zaghloul, 2004 Rosenstock, 1985 Urquhart, 1997 JD Bos, MM Meinardi, Exp Dermatol. 2000 Jun;9(3):165-9 D.W. Osborne and W.J. Lambert, Prodrugs for Dermal Delivery, K.B. Sloane ed., Marcel Dekker, New York 163-178 (1992) N. Li, X. Wu, W. Jia, M.C. Zhang, F. Tan, and J Zhang. Drug Dev Indust Pharm 38(8)985-994 D.W. Osborne and J.J. Henke, Pharmaceutical Technology 21(11)58-66(1997) Pudipeddi and Serajuddin, J. Pharm. Sci., 94(5) 929-939 (2005) A Patzelt, F Knorr, U Blume-Peytavi, W Sterry, J Lademann, Drug Discovery Today: Disease Mechanisms, 5(2)2008 pages e173-e181 Huang, 2018

When treating chronic skin diseases such as psoriasis topically, the benefits of developing a once-daily dosing product in terms of treatment adherence are offset by increased concerns about poor adherence among patients receiving once-daily topical application. Even roflumilast, a pharmacoactive substance with a 24-hour oral half-life due to its endogenous PK/PD properties, would benefit from a topically sustained-release formulation that significantly increases the duration of action, i.e., increases the plasma half-life of topical roflumilast.

Topical roflumilast formulations with longer half-lives and consistent delivery would be advantageous. Developing and providing pharmaceutical formulations containing roflumilast that can maintain consistent delivery and therapeutically effective dose levels despite poor adherence, such as missed doses of one, two, or more days after multiple topical applications, would be advantageous.

According to the present invention, hexylene glycol has been found to inhibit the crystal growth of roflumilast particles suspended or precipitated in formulations containing a pharmaceutically acceptable solvent, thus resulting in more consistent delivery of topically applied formulations for better skin permeability. In addition, including a solvent and a phosphate surfactant blend of dicetyl phosphate and ceteth-10 phosphate in topical formulations containing roflumilast increases the plasma half-life and duration of action. The increased half-life and duration of action alleviate concerns that poor adherence would reduce the success of the therapy and increase the tolerance for poor adherence of topically applied roflumilast.

The patent or application file must include at least one figure drawn in color. A copy of the published patent or patent application containing the color figure will be provided by the Office upon request and payment of the required fees.

Figure 1 shows the “dried” roflumilast crystals of sample 19-2 from ferrer-Interquim S. A. batch A14367P (the active pharmaceutical ingredient used in all examples herein). The roflumilast crystals are 0.01 mm to 0.02 mm in length. Figure 2 shows the roflumirlast crystals of sample 20-3 suspended in an equimolar aqueous solution after storage at room temperature for 6 weeks, under 10x magnification. The roflumirlast crystals are 0.01 mm to 0.02 mm in length. Figure 3 shows the roflumirlast crystals of sample 20-2 suspended in an aqueous solution of equimolar diethylene glycol monoethyl ether after storage at room temperature for six weeks. The roflumirlast crystals are 0.04 mm to 0.20 mm in length and 0.01 mm to 0.02 mm in width. Figure 4 shows the roflumirlast crystals of sample 20-3 suspended in an equimolar aqueous solution after storage at room temperature for 6 weeks, under 4x magnification. The roflumirlast crystals are 0.01 mm to 0.02 mm in length. Figure 5 shows the roflumirlast crystals of sample 21-2 suspended in an equimolar ethanol aqueous solution after storage at room temperature for 6 weeks. The roflumirlast crystals are 0.05 mm to 0.25 mm in length and 0.02 mm in width. Figure 6 shows the roflumirlast crystals of sample 21-3 suspended in an equimolar PEG 400 aqueous solution after storage at room temperature for six weeks. The roflumirlast crystals are 0.05 mm to 0.07 mm in length and 0.02 mm in width. Figure 7 shows the roflumirlast crystals of sample 21-4 suspended in an equimolar DMSO aqueous solution after storage at room temperature for six weeks. The roflumirlast crystals are 0.10 mm to 0.67 mm in length and 0.02 mm to 0.10 mm in width. Figure 8 shows the roflumirlast crystals of sample 21-5 suspended in an equimolar propylene glycol aqueous solution after storage at room temperature for 6 weeks. The roflumirlast crystals are 0.20 mm to 1.60 mm in length and 0.02 mm in width. Figure 9 shows the roflumirlast crystals of sample 20-1 suspended in an equimolar NMP:aqueous solution after storage at room temperature for 6 weeks. The roflumirlast crystals are 0.10 mm to 1.55 mm in length and 0.02 mm to 0.13 mm in width. Figure 10 shows the roflumirlast crystals of sample 21-1 suspended in an HG:NMP:water solution (molar fraction of water = 1.2) after storage at room temperature for 6 weeks. The roflumirlast crystals are 0.02 mm to 0.04 mm in length and 0.02 mm in width. Figures 11A and 11B show the roflumirlast particles precipitated in the cream composition after one freeze-thaw cycle. Figure 11A shows the roflumirlast particles of sample 36-1 precipitated in a cream composition containing diethylene glycol monoethyl ether (DEGEE) but not hexylene glycol. Three of the largest roflumirlast particles were measured (0.07 mm × 0.09 mm; 0.06 mm × 0.06 mm; and 0.10 mm × 0.05 mm) and found to have an average surface area of 5,000 square microns. Figure 11B shows the roflumirlast particles of sample 36-2 precipitated in a cream composition containing both diethylene glycol monoethyl ether (DEGEE) and hexylene glycol. Three of the largest roflumirasto particles were measured (0.05 mm × 0.03 mm; 0.05 mm × 0.03 mm; and 0.05 mm × 0.03 mm), and were found to have an average surface area of 1,500 square microns.

Roflumilast is a compound of formula (I),

In the formula, R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyrido-4-yl.
This compound has the chemical name N-(3,5-dichloropyrido-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: roflumilast).

Hexylene glycol (PharmaGrade. USP/NF) is 2-methyl-2,4-pentanediol of formula (II).

The emulsifier blend of cetearyl alcohol (CAS 67762 300), dicetyl phosphate (CAS 2197 639), and ceteth-10 phosphate (CAS 50643-20-4) is manufactured by Croda under the trade name CRODAFOS® CES. This commercially available emulsifier blend is a self-emulsifying wax, primarily composed of 10–20% dicetyl phosphate and 10–20% ceteth-10 phosphate, combined with the waxy substance cetearyl alcohol (which is a mixture of _cetyl alcohol ( _C16H34O ) and stearyl alcohol ( _C18H38O )). Self-emulsifying waxes form emulsions when blended with water. When _CRODAFOS® CES is added to water, it spontaneously forms an emulsion with a pH of approximately 3. A sodium hydroxide solution is added to raise the pH to the desired value.

This invention is directed towards inhibiting the growth of roflumilast crystals in a roflumilast-containing pharmaceutical composition containing a pharmaceutically acceptable solvent, including water, by adding hexylene glycol, a solvent, and/or a phosphate ester surfactant blend of dicetyl phosphate and ceteth-10 phosphate to the composition, and/or extending the half-life of roflumilast in the patient's body after administration.

For topical products designed to contain suspended roflumilast particles or crystals, the addition of hexylene glycol to the roflumilast-containing composition inhibits (i.e., prevents or substantially reduces) changes in particle size distribution over the product's shelf life, ensuring consistent bioavailability. For topical products designed to completely dissolve roflumilast, hexylene glycol inhibits the growth of precipitated roflumilast particles.

For drug products containing a fully dissolved active ingredient (API) over the product's shelf life under the storage conditions indicated on the label, precipitation of the active ingredient may occur if the product is formulated to maintain a significant thermodynamic drive. Typical storage conditions for topical medicinal creams are as follows: Store at room temperature (60°F/15°C to 80°F/26°C). Do not freeze. It is understood by product development scientists and regulatory reviewers that topical products will not always be stored over this temperature range. Therefore, the FDA requires all topical products to undergo freeze-thaw cycle and temperature deviation testing. The active ingredient is not required to remain in the solution, nor is it expected to remain, when the product is exposed to temperatures as low as -20°C, which is dramatically below the 15°C (60°F) storage conditions indicated on the label. Because topical products containing fully dissolved drugs are usually formulated near saturation, i.e., near maximum thermodynamic drive, most topical products will experience precipitation of the active ingredient during freeze-thaw cycle or temperature deviation testing. The addition of hexylene glycol prevents crystal growth of roflumilast in cases where precipitation occurs due to temperature deviations below the storage conditions indicated on the label. Inhibiting crystal growth ensures that once the product returns to controlled room temperature, all precipitated active ingredients will quickly revert to a completely dissolved state. Rapid reversion of precipitated roflumilast to a completely dissolved state ensures consistent and reproducible bioavailability, efficacy, and safety of topically applied products. Hexylene glycol can be added in amounts of 0.1% to 20% by weight, preferably 0.25% to 8% by weight, and most preferably 0.5% to 2% by weight.

To extend the half-life of roflumilast in the patient's body after administration, a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate, along with a solvent, is included in the formulation. The plasma half-life of roflumilast after intravenous administration in humans is approximately 15 hours; after oral administration, the plasma half-life is approximately 17–30 hours (see Bethke et al., High Absolute Bioavailability of the New Oral Phosphodiesterase-4 Inhibitor Roflumilast, International Journal of Clinical Pharmacology and Therapeutics, vol. 49, No.1, 2011, pp.51–57). The plasma half-life of roflumilast after topical administration of the formulation containing the self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate, along with the solvent, is 3.4–3.7 days (approximately 81–89 hours).

Topical Roflumilast product formulations that benefit from the addition of a self-emulsifying wax blend of hexylene glycol, dicetyl phosphate, and ceteth-10 phosphate, and/or solvents, include, but are not limited to, aerosols, foams, sprays, emulsions (which may also be called creams, lotions, or ointments), gels (two-phase or single-phase), liquids, ointments, pastes, shampoos, suspensions, and systems. These are Tier 2 terms in the Compendia Taxonomi (United States Pharmacopeia <1151>) relating to dosage forms containing pharmaceutically active ingredients.

Roflumilast formulations can be prepared by methods known in the art (see, for example, Patent No. 298 and U.S. Patent Application Publication No. 14/075,035).
Preferably, a self-emulsifying wax blend of hexylene glycol, dicetyl phosphate, and ceteth-10 phosphate, and/or a solvent, is added to a composition containing 0.005 to 2.0% roflumirasto, which can be in one of the following forms:
Oil-in-water emulsions: Products can be formulations added to an emulsion comprising a self-emulsifying wax blend of hexylene glycol, dicetyl phosphate, and ceteth-10 phosphate, and/or a solvent, which comprises a separated phase of hydrophobic components and a continuous aqueous phase containing water and optionally one or more polar hydrophilic excipients, as well as additional solvents, cosolvents, salts, surfactants, emulsifiers, and other components. These emulsions may contain water-soluble or water-swellable polymers to help stabilize the emulsion. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

Thickened aqueous gels: These systems include an aqueous phase thickened with a suitable natural, modified natural, or synthetic thickener, such as those listed below. Alternatively, thickened aqueous gels can be thickened using a suitable polyethoxylate alkyl chain surfactant or other nonionic, cationic, or anionic systems.

Thickened hydroalcoholic gels: These systems contain a blend of water and alcohol as a polar phase, thickened with suitable natural, modified natural, or synthetic polymers as described below. Alternatively, thickened hydroalcoholic gels can be thickened using suitable polyethoxylated alkyl chain surfactants or other nonionic, cationic, or anionic systems. The alcohol may be ethanol, isopropyl alcohol, or other pharmaceutically acceptable alcohols.

Hydrophilic gels: These are systems in which the continuous phase contains at least one water-soluble or water-dispersible hydrophilic component other than water. The formulation may also contain up to 60% by weight of water. Higher levels may be appropriate in some compositions. Suitable hydrophilic components include one or more glycols, e.g., polyols, e.g., glycerin, propylene glycol, butylene glycols, polyethylene glycols (PEG), random or block copolymers of ethylene oxide, propylene oxide and/or butylene oxide, polyalkoxylated surfactants having one or more hydrophobic moieties per molecule, silicone copolyols, blends of ceteareth-6 and stearyl alcohol, and combinations thereof.

Water-in-oil emulsions: The compositions may be formulations in which Roflumilast is incorporated into an emulsion comprising a continuous phase of hydrophobic components and an aqueous phase containing water and optionally one or more polar hydrophilic carriers and salts or other components. These emulsions may contain oil-soluble or oil-swelling polymers and one or more emulsifiers to help stabilize the emulsion. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

Hydrophilic or hydrophobic ointments: The composition is formulated with a hydrophobic base (e.g., petrolatum, thickener, or gelled water-insoluble oil) and may contain a small amount of water-soluble phase. Hydrophilic ointments generally contain one or more surfactants or humectants.

Solvents Compositions according to the present invention may contain one or more solvents or co-solvents to obtain a desired level of solubility of the active ingredient in a topical product. The solvent may also modify the skin penetration or activity of other excipients contained in the formulation. Solvents include, but are not limited to, acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methylpyrrolidinone, polyethylene glycol, glycerol, propylene glycol, and SD alcohol.

Moisturizers Compositions according to the present invention may contain humectants to increase the level of hydration. The humectant may be a hydrophilic material containing a wetting agent, or it may be a hydrophobic material containing a emollient. Suitable humectants include 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl ester waxes, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, monostearate This includes, but is not limited to, glyceryl phosphate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, and stearyl alcohol.

Surfactants and Emulsifiers Compositions according to the present invention may optionally contain one or more surfactants to emulsify the composition and help wet the surface of the active ingredient or excipient. As used herein, the term “surfactant” means an amphiphilic substance (a molecule having both covalently bonded polar and nonpolar regions) that can reduce the surface tension of water and/or the interfacial tension between water and an immiscible liquid. The surfactants include, but are not limited to, the following surfactants: alkylaryl sodium sulfonates, Amerchol-CAB, ammonium lauryl sulfate, apricot kernel oil PEG-6 esters, Arlacel, benzalkonium chloride, Ceteareth-6, Ceteareth-12, Ceteareth-15, Ceteareth-30, cetearyl alcohol/ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-2, ceteth-20, ceteth-23, choleth-24 (chol (eth-24), cocamide ether sulfate, cocamine oxide, cocobetaine, cocodiethanolamide, cocomonoethanolamide, cococaprylate/caprate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamide monoethanolamine sulfosuccinate, sodium doxate, laureth-2, laureth-23, laureth-4, lauric acid diethanolamide, lecithin, methoxyPEG-16 (mehoxy PEG-16), methyl gluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2, oleth-20, PEG 6-32 stearate, PEG-100 stearate, PEG-12 glyceryl laurate, PEG-120 methyl glucose dioleate, PEG-15 cocamine, PEG-150 distearate, PEG-2 stearate, PEG-20 methyl glucose sesquistearate, PEG-22 methyl ether, PEG-25 propylene glycol stearate, PEG-4 dilaurate, PEG-4 laurate, PEG-45/dodecyl glycol copolymer, PEG-5 oleate, PEG-50 stearate, PEG-54 hydrogenated castor oil, PEG-6 isostearate, PEG-60 hydrogenated castor oil, PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate, PEGoxol 7 Stearate, Pentaerythritol Cocoate, Poloxamer 124, Poloxamer 181, Poloxamer 182, Poloxamer 188, Poloxamer 237, Poloxamer 407, Polyglyceryl-3 Oleate, Polyoxyethylene Alcohols, Polyoxyethylene Fatty Acid Esters, Polyoxyl 20 Cetostearyl Ether, Polyoxyl 40 Hydrogenated Castor Oil, Polyoxyl 40 Stearate, Polyoxyl 6 and Polyoxyl 32, Polyoxyl Glyceryl Stearate, Polyoxyl Stearate, Polysol Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80, PPG-26 oleate, PROMULGEN (trademark) 12, Propylene glycol diacetate, Propylene glycol dicaprylate, Propylene glycol monostearate, Sodium xylene sulfonate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan monostearate, Steareth-2, Steareth-20, Steareth-21, Steareth-40, Fat glycerides, and emulsifying waxes. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

Polymers and Thickeners: For specific applications, it may be desirable to incorporate products thickened with soluble, swelling, or insoluble organic polymeric thickeners, such as natural and synthetic polymers, or inorganic thickeners, such as acrylate copolymers, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxyvinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline waxes, and methylcellulose.

Additional Components The compositions according to the present invention may be formulated with additional components conventionally found in cosmetic and topical pharmaceutical products, such as fillers, carriers, and excipients. Additional components that may be added to the compositions include, but are not limited to, defoamers, preservatives (e.g., p-hydroxybenzoic acid esters, benzyl alcohol, phenylmercury salts, chlorocresol), antioxidants, chelating agents, stabilizers, buffers, pH adjusting solutions, skin penetration enhancers, film-forming agents, dyes, pigments, diluents, bulking agents, fragrances, and other excipients for improving stability or aesthetics.

The compositions according to the present invention may be formulated with additional active agents depending on the disease being treated. Additional active agents include, but are not limited to, the following: NSAIDs (e.g., aspirin, ibuprofen, ketoprofen, naproxen), apremilast, JAK inhibitors (e.g., tofacitinib, ruxolitinib, oclacit), leukotriene inhibitors (e.g., diloton, zafirlukast, montelukast), mast cell stabilizers (e.g., nedocromil, cromolin sodium, ketotifen, pemirolast), anthralines (ditranol), azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarate esters. Corticosteroids (e.g., acromethasone, amcinonide, betamethasone, clobetasol, crocoltolone, mometasone, triamcinolone, fluocinolone, fluocinonide, flulandrenolide, diflorazone, desonide, desoxymethasone, dexamethasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, prednicarbate, prednisone), corticotropins, vitamin D analogues (e.g., calcipotriene, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, colchicine, bronchodilators (e.g., β-agonists, anticholinergics, theophylline), and antibiotics (e.g., erythromycin, ciprofloxacin, metronidazole).

Dosage and Administration Compositions according to the present invention can be administered by any suitable route of administration, including but not limited to oral, rectal, parenteral (e.g., intradermal, subcutaneous, intramuscular, intravenous, intramedullary, intraarterial, intrathecal, epidural), ocular, inhalation, spray, skin (topical), transdermal, and mucosal (e.g., sublingual, buccal, nasal). In a preferred embodiment, the composition is administered topically.

Appropriate pharmaceutical dosage forms include, but are not limited to, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels, foamy substances, transdermal patches, and solutions (e.g., for injection, or oral use).

This composition preferably contains 0.005 to 2% w/w, more preferably 0.05 to 1% w/w, and most preferably 0.1 to 0.5% w/w of roflumilast, a salt of roflumilast, N-oxide of roflumilast, or a salt thereof per dose unit.

The composition preferably contains hexylene glycol in an amount of 0.1% to 20% w/w, more preferably 0.25% to 8% w/w, and most preferably 0.5% to 2% w/w.
The composition preferably contains a phosphate ester surfactant in the formulation, in an amount sufficient to produce a stable emulsion having a uniform sphere size. The concentration of the phosphate ester surfactant can generally be any concentration from 1.0% to 25% w/w. The preferred concentration may differ with respect to different dosage forms. In a preferred embodiment, when the formulation is a cream or ointment, the concentration of the phosphate ester surfactant is 2.5% to 20%, a more preferred concentration range is 5% to 15%, and the most preferred concentration is about 10% w/w. When the formulation is the formation of a foamy substance, the concentration is preferably 1.0% to 10%, more preferably 1.0% to 10%, and most preferably 2%. Preferably, the phosphate ester surfactant is provided in a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

The composition preferably contains a sufficient amount of solvent to obtain the desired level of solubility of the active ingredient in the formulation. The solvent is preferably in an amount of 10-30% (w/w). The solvent-to-water ratio is preferably 1:10-20:1. Preferably, the solvent is diethylene glycol monoethyl ether (DEGEE).

Topical formulations containing roflumilast are typically applied to the skin in an amount sufficient to obtain the desired pharmacological effect for improving signs and/or symptoms of a medical disorder. The amount of formulation applied may vary depending on the amount of roflumilast contained in the formulation, the concentration of roflumilast in the formulation, and the frequency at which the formulation is intended to be applied. Generally, the formulation is applied weekly to several times daily, preferably every other day to three times daily, most preferably once or twice daily.

The composition may be used in veterinary medicine and human medicine for the treatment and prevention of all diseases that are considered treatable or preventable by using roflumilast, including but not limited to the following: acute and chronic airway disorders, e.g., bronchitis, allergic bronchitis, asthma and COPD; proliferative, inflammatory and allergic skin diseases, e.g., psoriasis, scalp psoriasis or reverse psoriasis (inverse) Psoriasis), irritant and allergic contact dermatitis, hand eczema, atopic dermatitis, seborrheic dermatitis, lichen simplex, sunburn, aphthous ulcers, lichen planus, vitiligo, pruritus in the genital or anal area, alopecia areata, hypertrophic scarring, discoid lupus erythematosus, follicular and widespread pyoderma, endogenous and exogenous acne, rosacea, disorders based on excessive release of TNF and leukotrienes, cardiac disorders that can be treated with PDE inhibitors, inflammation in the gastrointestinal or central nervous system, eye disorders, disorders that can be treated by the tissue relaxant effect of PDE inhibitors, and other proliferative, inflammatory and allergic skin disorders; as well as immune-mediated diseases, including arthritis, such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and psoriatic arthritis. Preferably, the composition is used to treat proliferative, inflammatory, and allergic skin diseases, such as psoriasis (vulgaris), eczema, acne, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, and pyoderma.

The composition may contain additional active agents suitable for treating the patient's disease. For example, when treating proliferative, inflammatory, and allergic skin diseases, the composition may additionally contain anthraline (ditranol), azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil (Propylthoracil), 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarates, corticosteroids (e.g., acromethasone, amcinonide, betamethasone, clobetasol, crocoltron). This may include (Clocotolone), mometasone, triamcinolone, fluocinolone, fluocinonide, flulandrenolide, diflorazone, desonide, desoxymethasone, dexamethasone, halcinonide, halobetazole, hydrocortisone, methylprednisolone, prednicarbate, prednisone), corticotropin, vitamin D analogs (e.g., calcipotriene, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, colchicine, adalimumab, ustekinumab, infliximab, and/or antibiotics.

Formulations for topical application containing roflumilast can be prepared by processes typically used in the technical field of pharmaceutical formulations for topical application. To prepare single-phase formulations, such as liquids, the components of the formulation can be combined and mixed until a homogeneous solution or suspension of the active ingredient is obtained. To prepare multi-phase formulations, such as emulsions, the components of, for example, the aqueous and oil phases can be combined separately and mixed until a homogeneous solution is obtained, and then the aqueous and oil solutions can be combined and mixed, for example, by shear mixing, to form the formulation. One or more drug active ingredients can be dissolved (molecularly dispersed), complexed, associated with excipients or other active ingredients, or in particulate form (amorphous or crystalline). The oil phase can be added to the aqueous phase, or the aqueous phase can be added to the oil phase. The phases can be combined and mixed, for example, at a high temperature of 50–90°C, at room temperature of 20–30°C, or at a temperature between room temperature and high temperature.

The following examples are provided to enable those skilled in the art to prepare and use the methods and compositions of the present invention. These examples are not intended to limit the scope of what the inventors consider to be their invention. Additional advantages and modifications will be readily apparent to those skilled in the art.

Example 1
Several milligrams of roflumilast API (batch A14367P from Interquim S.A.) dried powder were gently tapped onto a microscope slide, the coverslip was moved to the appropriate position, and the crystal habit and grain size of the API were examined using a polarizing microscope with a 10x objective lens (Figure 1, microscope sample 19-2).

0.0092 grams of roflumilast (batch A14367P from Interquim S.A.) were weighed into a liquid scintillation vial. An equimolar blend of hexylene glycol (lot 1 AC0818, Spectrum) and distilled water was added dropwise to the vial containing roflumilast, mixing to produce a suspension of roflumilast exceeding its solubility limit. The equimolar blend consisted of 86.7% hexylene glycol and 13.3% water on a weight/weight percentage basis. After mixing each addition of the hexylene glycol:water blend, the tightly capped vial was returned to a water bath set to 25°C. 0.7962 grams of the equimolar hexylene glycol:water blend was required to completely dissolve 0.0092 grams of roflumilast and give an equimolar 1.14% roflumilast (wt/wt%) solution in hexylene glycol:water. 0.0064 g of roflumilast was added to this sample (labeled 12-3) to form a finely dispersed suspension at 25°C. The vial was then stored undisturbed at approximately 15–18°C and protected from light for 6 weeks. The roflumilast crystal sample was removed from the vial, placed on a microscope slide (with a coverslip), and examined using a polarizing microscope with a 10x objective lens (Figure 2, Microscoped sample 20-3).

0.0111 grams of roflumilast (batch A14367P from Interquim S.A.) was weighed into a liquid scintillation vial. An equimolar blend of diethylene glycol (DEGEE) (Transcutol P, lot 146063, Gattefosse) and distilled water was added dropwise to the vial containing roflumilast, mixing to produce a suspension of roflumilast exceeding its solubility limit. The equimolar blend was 88.3% DEGEE and 11.7% water on a weight/weight percentage basis. After mixing each addition of the DEGEE:water blend, the tightly capped vial was returned to a water bath set to 25°C. 0.2477 grams of an equimolar DEGEE:water blend was required to completely dissolve 0.0111 grams of roflumilast, yielding an equimolar 4.29% roflumilast (wt/wt%) solution in DEGEE:water. This sample (labeled 13-1) was a solution of roflumilast at 25°C, and the vial was then stored undisturbed at approximately 15–18°C, protected from light for 6 weeks. Roflumilast crystals precipitated due to the lower storage temperature. The roflumilast crystal sample was removed from the vial, placed on a microscope slide (with a coverslip), and then examined using a polarizing microscope with a 10x objective lens (Figure 3, Microscoped sample 20-2).

Example 2
0.0092 grams of roflumilast (batch A14367P from Interquim S.A.) were weighed into a liquid scintillation vial. An equimolar blend of hexylene glycol (lot 1 AC0818, Spectrum) and distilled water was added dropwise to the vial containing the roflumilast, mixing to produce a suspension of roflumilast exceeding its solubility limit. The equimolar blend consisted of 86.7% hexylene glycol and 13.3% water on a weight/weight percentage basis. After mixing each addition of the hexylene glycol:water blend, the tightly capped vial was returned to a water bath set to 25°C. 0.7962 grams of the equimolar hexylene glycol:water blend was required to completely dissolve 0.0092 grams of roflumilast and give an equimolar 1.14% roflumilast (wt/wt%) solution in hexylene glycol:water. 0.0064 g of roflumilast was added to this sample (labeled 12-3) to form a finely dispersed suspension at 25°C. The vial was then stored undisturbed at approximately 15–18°C and protected from light for 6 weeks. The roflumilast crystal sample was removed from the vial, placed on a microscope slide (with a coverslip), and then examined using a polarizing microscope with a 4x objective lens (Figure 4, Microscoped sample 20-3).

0.0260 grams of roflumilast (batch A14367P from Interquim S.A.) were weighed into a liquid scintillation vial. 1.0705 grams of ethanol:water blend (74.98% ethanol and 25.02% water or 95 vol% Everclear, on a weight/weight percentage basis) were added to produce a dispersion of roflumilast in the ethanol:water blend exceeding its solubility limit. This sample (labeled "Alc" page 2) was then stored undisturbed at approximately 15–18°C and protected from light for 6 weeks. The roflumilast crystal sample was removed from the vial, placed on a microscope slide (with a coverslip), and then examined using a polarizing microscope with a 4x objective lens (Figure 5, microscopic sample 20–3).

0.0180 grams of roflumilast (batch A14367P from Interquim S.A.) were weighed into a liquid scintillation vial. Polyethylene glycol 400 (lot 1DE0880, Spectrum) was added dropwise to the vial containing roflumilast, mixing to produce a suspension of roflumilast exceeding its solubility limit. After mixing each addition of polyethylene glycol 400, the tightly sealed vial was returned to a water bath set to 25°C. 0.5486 grams of propylene glycol 400 were required to completely dissolve 0.0180 grams of roflumilast and give a 3.18% roflumilast solution in polyethylene glycol 400 solution. This sample (labeled "PEG 400," page 1) was a solution at 25°C and then stored undisturbed at approximately 15–18°C, protected from light for 6 weeks. The roflumirlast crystals precipitated due to the lower storage temperature. A sample of the roflumirlast crystals was removed from the vial, placed on a microscope slide (with a coverslip), and then examined using a polarizing microscope with a 4x objective lens (Figure 6, microscope sample 21-3).

0.0103 grams of roflumilast (batch A14367P from Interquim S.A.) were weighed into a liquid scintillation vial and mixed with 0.2501 grams of dimethyl sulfoxide (lot US150, Gaylord Chemical) at 25°C to obtain a 28.5% solution of roflumilast. This sample (labeled "DMSO," page 2) was then stored undisturbed at approximately 15–18°C and protected from light for 6 weeks. The precipitated roflumilast crystals were removed from the vial, placed on a microscope slide (with a coverslip), and then examined using a polarizing microscope with a 4x objective lens (Figure 7, microscope samples 21-4).

0.0061 grams of roflumilast (batch A14367P from Interquim S.A.), 1.9332 grams of propylene glycol (lot 1EC0004, Spectrum), and 0.2335 grams of distilled water were mixed at 25°C to initially form a clear solution. The composition of the sample was 0.28% roflumilast, 88.97% propylene glycol, and 10.75% water on a weight/weight % basis. After storage at 25°C for 105 minutes, a “dust” of fine roflumilast crystals was observed at the bottom of the vial. After 6 days, additional crystals settled at the bottom of the vial. This sample (labeled 7-2) was then stored undisturbed at approximately 15–18°C and protected from light for 6 weeks. The precipitated roflumirlast crystal sample was removed from the vial, placed on a microscope slide (along with a coverslip), and then examined using a polarizing microscope with a 4x objective lens (Figure 8, microscope sample 21-5).

Example 3
In an equimolar aqueous solution of N-methylpyrrolidone containing roflumilast beyond drug saturation, dramatically greater roflumilast crystal growth was observed compared to a 12:4:3 (wt/wt/wt) blend of hexylene glycol:N-methylpyrrolidone:water (1.2 mole fraction water) solution containing roflumilast added beyond its solubility limit.

0.0202 grams of roflumilast (batch A14367P from Interquim S.A.) was mixed in a liquid scintillation vial with 0.0682 grams of an equimolar N-methyl-2-pyrrolidone:water blend. The equimolar blend consisted of 84.5% N-methyl-2-pyrrolidone (lot SYYN-HJ, TCI) and 15.5% water on a weight/weight percentage basis. 22.85% roflumilast in the equimolar N-methyl-2-pyrrolidone:water dissolved completely at 25°C. This sample (indicated as 13-2) was then stored undisturbed at approximately 15–18°C and protected from light for 6 weeks. Due to the lower storage temperature, roflumilast crystals precipitated. The roflumirlast crystal sample was removed from the vial, placed on a microscope slide (along with a coverslip), and then examined using a polarizing microscope with a 4x objective lens (Figure 10, Microscoped sample 20-1).

A sample of 0.8152 grams of roflumilast (batch A14367P from Interquim S.A.), 60.8% hexylene glycol (lot 1AC0818, Spectrum), 20.0% N-methyl-2-pyrrolidone (lot SYYN-HJ, TCI), and 15.6% distilled water was mixed on a weight/weight percentage basis. This sample (indicated as 13-4) was a finely dispersed suspension of roflumilast at 25°C. The sample was then stored undisturbed at approximately 15–18°C and protected from light for 6 weeks. The roflumilast crystalline sample was removed from the vial, placed on a microscope slide (with a coverslip), and then examined using a polarizing microscope with a 4x objective lens (Figure 11, microscope sample 21-1).

Example 4
Loflumilast Cream was prepared according to the following formulation.

After preparation, 0.4222 grams of formulation 1 was sealed in a 1.0 mL CryoTube® vial and labeled 36-1. Similarly, 0.3961 grams of formulation 2 was sealed in a 1.0 mL CryoTube® vial and labeled 36-2. The two CryoTube® vials were joined end-to-end in an envelope and placed in a freezer for 17.5 hours. Immediately after removal from the freezer, microscope slides were prepared for each sample. After "thawing" the samples to room temperature (18°C), micrographs were taken to characterize the differences in the growth of precipitated roflumirist crystals. See Figures 11A and 11B.

Example 5
The formulation of the present invention (hereinafter referred to as Formulation 3) was prepared by combining 0.3% w/w loflumilast with Crodafos CES (a phosphate ester surfactant blend of dicetyl phosphate and ceteth-10 phosphate combined with cetostearyl alcohol), and adding diethylene glycol monoethyl ether and other components to create a fully commercially viable formulation. This formulation was buffered with NaOH and water to obtain a pH of 5.5. Formulation 3 is the same as Formulation 2, except that Formulation 3 contains 0.3% loflumilast, while Formulation 2 contains 0.5% loflumilast.

A formulation not of the present invention (hereinafter referred to as Comparative Formulation 4) was prepared by combining 0.3% w/w of roflumilast with Crodafos CES (a phosphate ester surfactant blend of dicetyl phosphate and ceteth-10 phosphate combined with cetostearyl alcohol) and water. The formulation was buffered with NaOH to obtain a pH of 5.5. Comparative Formulation 4 does not contain diethylene glycol monoethyl ether or hexylene glycol.

A formulation other than that of the present invention (hereinafter referred to as comparative formulation 5) was prepared by combining it with roflumilast at a concentration of 0.2%. This formulation is the closest prior art formulation known to the inventors and is disclosed in Example 3 of Bolle et al.'s U.S. Patent Application Publication No. 2006/0084684.

A formulation other than the present invention (hereinafter referred to as comparative formulation 6) was prepared by combining it with roflumilast at a concentration of 0.3%. This formulation contains potassium cetyl phosphate (Crodafos MCK) as an emulsifier, but does not contain dicetyl phosphate or ceteth-10 phosphate, which are phosphate ester emulsifiers contained in the self-emulsifying wax Crodafos CES.

The composition of these compounds is shown in Table 1 below.

Glyceryl stearate/PEG-100 stearate is a nomenclature used by the U.S. Food and Drug Administration to describe nonionic emulsifier blends marketed under the trade names Arlacel® 165 and Tego Care® 165.

Medium-chain triglycerides are a nomenclature used by the U.S. Food and Drug Administration to describe caprylic/capric triglyceride, a cosmetic ingredient marketed under trade names including Miglyol® 812 and Crodamol® GTCC.

Example 6 - Excretion kinetics of the formulation of Example 5 after 14 days of administration Male and female pigs (Gottingen Minipig® breed) are ordered to weigh 8-12 kg upon arrival. The day before administering one dose of the semi-solid topical cream formulation of Example 5, the hair is shaved from the back of each animal. The pigs are sedated for the shaving procedure. Care is taken to avoid scraping the skin.

One of the cream formulations from Example 5, at a dose of 2 (2) grams per kg of pig body weight, is distributed onto a shaved skin area by gentle rubbing using a glass stirring rod or stainless steel spatula. The cream formulation is applied evenly in a thin, uniform film, starting in the scapular region, covering the test site, and moving towards the tail. The width of the test site area is divided bilaterally by the spine. Six pigs (three males and three females) are administered either formulation 3, comparative formulation 4, comparative formulation 5, or comparative formulation 6 once daily for 14 days. Blood is collected from the anterior vena cava through the thoracic inlet or from another suitable vein 17, 18, 19, and 20 days after the last dose administration to determine the elimination half-life of roflumilast from these four cream formulations.

As shown in Table 2, formulations containing the phosphate ester surfactant Crodafos CES, hexylene glycol, and the solvent diethylene glycol monoethyl ether showed a significant increase in the plasma half-life and duration of action of roflumilast after topical application. The closest prior art formulation (comparative formulation 5) and comparative formulation 6 (a cream formulation in which Crodafos CES (a phosphate ester surfactant blend of dicetyl phosphate and ceteth-10 phosphate combined with cetostearyl alcohol) was replaced with Crodafos MKC (a phosphate ester surfactant potassium cetyl phosphate combined with cetostearyl alcohol)) had a reduced plasma half-life compared to formulation 3 containing Crodafos CES. Comparative formulation 4, which did not combine hexylene glycol and diethylene glycol monoethyl ether with cetostearyl alcohol in a phosphate ester surfactant blend of dicetyl phosphate and ceteth-10 phosphate (Crodafos CES), did not exhibit an increased half-life and duration of roflumirist action after topical application in pigs.

Example 7 - Elimination kinetics of formulation 3 after 84 days of administration in psoriasis patients. Roflumilast cream was prepared according to the following formulation.

A parallel-group, double-blind, vehicle-controlled trial was conducted in which ARQ-151 cream 0.3% (composition 3 in Example 5), ARQ-151 cream 0.15% (composition 7), or vehicle cream was administered via 84-day QD to subjects with chronic plaque psoriasis involving 2–20% body surface area (BSA).

Approximately 300 subjects were enrolled across approximately 30 trial sites in the United States and Canada. Subjects were adult (≥18 years) males or females with chronic plaque psoriasis. Subjects had at least a mild ('2') investigator-assessed overall disease severity (IGA) at baseline. Subjects with a 'mild' (2) IGA (2) accounted for 20% of the total enrollment. Subjects with a 'severe' (4) IGA accounted for 15% of the total enrollment. Subjects had a body surface area (BSA) of chronic plaque psoriasis of at least 2% and not greater than 20%. All psoriatic lesions on subjects, including face, trunk, genital/skin folds, or limbs (excluding scalp), were treated. Palms and soles were treated but were not counted in any efficacy measurements (IGA, BSA, mPASI). For subjects with intertriginous involvement and at least a 'mild' (IGA ≥ 2) severity of intertriginous lesions at baseline, the 'I-IGA' score was recorded at weeks 4, 6, 8, and 12. The same IGA used for the primary endpoint (whole body) was also used for the 'Intertriginous Lesion IGA Score' (I-IGA), but only the intertriginous region was evaluated for I-IGA; the rest of the body was not evaluated.

Blood samples were collected from all subjects at all facilities prior to administration on day 1 (baseline), week 4 (day 29), and week 12 (day 85). Analysis of the collected PK data was performed using a CFR 21 Part 11 compliant software package (Phoenix WinNonlin version 8.1) that fully complies with ICH-GCP. Samples from all subjects within the PK population were evaluated. Any subjects or data excluded from the PK analysis were identified along with the reason for exclusion in this PK report. BSA was averaged based on measured BSA values at baseline, week 2, week 4, week 6, and week 8, screening values, and values at week 12 and week 16, excluding values from any other unscheduled visits. Four subjects participated in any phase upon completion of a study to assess roflumilast and N-oxide excretion at the end of treatment, but only three had quantifiable concentrations of roflumilast and N-oxide. From the three subjects, the terminal rate constants (lambda z, λz) were determined by the slope of the regression line of the concentration-time data transformed using the natural logarithm. The terminal half-life (t¹/²) was calculated as ln(2)/λz.

Concentration values reported as BLQ (<0.100 for roflumilast and N-oxide) were reported as below the limit of quantification (BLQ) in the concentration data list and were considered non-numeric. Non-numeric values were ignored for concentrations calculated using nominal time summary statistics. Summary statistics (i.e., N, arithmetic mean, SD, CV%, minimum, median, maximum, geometric mean, geometric SD, and 95% confidence intervals for both arithmetic and geometric means) were calculated for plasma concentrations for each analyte, nominal day, and dose intensity. All concentrations and descriptive statistics were reported in three significant figures.

Following multiple topical administrations of ARQ-151 to areas of psoriasis vulgaris covering 2–20% BSA, evidence of systemic plasma exposure to roflumilast and N-oxide was observed (Table 3). The mean BSA treated was approximately 5% for both treatment groups (Table 3). The mean pre-administration roflumilast concentrations were 1.82 and 1.50 ng/mL after topical administration of ARQ-151 0.3% on days 29 and 85, respectively (Table 3). When normalized for treated BSA, the mean concentrations were 0.424 and 0.344 ng/mL, respectively. The mean pre-administration roflumilast concentrations were 1.12 and 0.878 ng/mL after topical administration of ARQ-151 0.15% on days 29 and 85, respectively. After normalizing the treated BSA, the mean concentrations were 0.293 and 0.250 ng/mL, respectively.

The mean pre-administration N-oxide concentrations were 11.2 and 9.18 ng/mL after topical administration of ARQ-151 0.3% on days 29 and 85, respectively. Normalizing for treated BSA, the mean concentrations were 2.66 and 2.10 ng/mL, respectively. The mean pre-administration N-oxide concentrations were 6.53 and 4.63 ng/mL after topical administration of ARQ-151 0.15% on days 29 and 85, respectively. Normalizing for treated BSA, the mean concentrations were 1.68 and 1.28 ng/mL, respectively. Overall, the mean pre-administration plasma concentrations of roflumilast and N-oxide were within two times each other on days 29 and 85.

In patients with atopic dermatitis (n=6) with an average BSA-treated area of 6.5%, the arithmetic mean (AM) pre-administration concentration at day 15 after topical administration of ARQ-151 0.15% was 1.99 ng/mL (ARQ-151-102 study), with a normalized dose of 0.306 ng/mL. The geometric mean (GM) value was 0.874 ng/mL, with a normalized value of 0.134 ng/mL. A comparison with the dose-normalized pre-administration concentrations at day 29 in this study after 0.15% administration in subjects with psoriasis vulgaris treated with 5% BSA (AM value of 0.293 ng/mL and GM value of 0.187 ng/mL) showed that they were within 10% of each other, suggesting minimal difference in systemic exposure between the two disease states. Due to the flat nature of plasma concentrations at steady state, AUC values can be extrapolated by multiplying the pre-administration concentration by 24. From the ARQ-151-102 study, the AM AUC Class value was 53.9 and the GM value was 21.9 h ^* ng/mL. Using the pre-administration values of AM and GM, the extrapolated AUC values for the ARQ-151-102 study are estimated to be 47.8 or 21.0 ^h* ng/mL, respectively—which is in good agreement with the measured values. From this study, using the pre-administration concentration on day 29, the extrapolated AUC values for AM and GM would be 26.9 and 18.6 h* ng/mL, respectively.

Pre-administration plasma concentrations of roflumilast increased approximately 1.6-fold and 1.7-fold on days 29 and 85, respectively, within a twofold increase in administration intensity. Similarly, pre-administration plasma concentrations of roflumilast N-oxide (N-oxide) increased approximately 1.7-fold and 2.0-fold on days 29 and 85, respectively, within a twofold increase in administration intensity.

In general, the average plasma concentration before N-oxide administration was 5.3 to 6.2 times higher than the plasma concentration before parental administration, which is consistent with previous studies.
Three subjects participated in any phase of the study completion to evaluate the elimination of roflumilast and N-oxide at the end of the treatment. The half-lives for both roflumilast and N-oxide were approximately 3.6 days (see Table 4).

As described above, the plasma half-life of roflumilast after intravenous administration is approximately 15 hours; after oral administration, the plasma half-life is approximately 17–30 hours. The plasma half-life of roflumilast after topical administration of a formulation containing hexylene glycol, diethylene glycol monoethyl ether (Transcutol P), and a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate is 3.4–3.7 days (approximately 81–89 hours). The increased half-life and duration of action alleviate concerns that poor adherence would reduce therapeutic success and increase the tolerance for poor adherence of topically applied roflumilast.
This specification includes the disclosure of the following inventions.
[Item 1] A method for improving the delivery of a roflumilast composition and extending its plasma half-life, comprising adding hexylene glycol, diethylene glycol monoethyl ether, dicetyl phosphate, and ceteth-10 phosphate to a composition containing roflumilast.
[Item 2] A method according to Item 1, wherein the composition comprises suspended roflumirist particles.
[Item 3] The method according to Item 1, wherein the hexylene glycol is added in an amount of 0.1 to 20% w/w.
[Item 4] A method according to Item 1, wherein the dicetyl phosphate and ceteth-10 phosphate are added as part of a surfactant blend.
[Item 5] A method according to Item 5, wherein the surfactant blend comprises dicetyl phosphate, ceteth-10 phosphate, and cetearyl alcohol.
[Item 6] The method according to Item 5, wherein the surfactant blend is present in an amount of 10% w/w.
[Item 7] A method according to Item 1, wherein the roflumilast composition is selected from the group consisting of oil-in-water emulsions, thickened aqueous gels, thickened hydroalcohol gels, hydrophilic gels, and hydrophilic or hydrophobic ointments.
[Item 8] A method according to Item 1, wherein the roflumilast composition further comprises an additional active agent selected from the group consisting of anthraline, azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarate esters, corticosteroids, corticotropin, vitamin D analogues, acitretin, tazarotene, cyclosporine, resorcinol, colchicine, adalimumab, ustekinumab, infliximab, bronchodilators, and antibiotics.
[Item 9] A method according to Item 1, wherein the composition comprises a carrier suitable for topical administration.
[Item 10] A method for improving the therapeutic outcomes of treatment with roflumilast, comprising topically administering a composition comprising hexylene glycol, diethylene glycol monoethyl ether, dicetyl phosphate, ceteth-10 phosphate, and roflumilast to a patient requiring such treatment at least once daily, wherein the plasma concentration of roflumilast decreases by less than 50% if the patient misses two consecutive doses.
[Item 11] The method according to Item 10, wherein the patient is suffering from atopic dermatitis.
[Item 12] A method according to Item 10, wherein the plasma concentration of roflumilast decreases by less than 50% after three days of missed doses.
[Item 13] The method described in Item 10, wherein the composition is as follows:
Loflumilast 0.3% w/w
White petrolatum 10.0% w/w
Isopropyl palmitate 5.0% w/w
Cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate 10.0% w/w
Hexylene glycol 2.0% w/w
Diethylene glycol monoethyl ether 25.0% w/w
Methylparaben 0.2% w/w
Propylparaben 0.05% w/w, and
Purified water: Sufficient amount up to 100 (47.25%)
A method that includes and adjusts the pH to 5.5.

Claims (10)

A pharmaceutical composition for use in treating inflammatory skin diseases by topical application to inflammatory skin diseases,
i) 0.05-1.0% w/w of roflumilast,
ii) water;
A pharmaceutical composition comprising iii) diethylene glycol monoethyl ether, and iv) an emulsifier blend containing cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, wherein topical application is performed every other day, and the plasma half-life of roflumilast after topical application of the pharmaceutical composition is 3 to 4.5 days. The pharmaceutical composition according to claim 1, which is a cream or foamy substance. The pharmaceutical composition according to claim 1, wherein the plasma half-life of roflumilast is approximately 3 to approximately 3.7 days. The pharmaceutical composition according to claim 1, comprising an emulsifier blend in an amount of 1.0 to 25% w/w. The pharmaceutical composition according to claim 4, comprising a 10% w/w emulsifier blend. The pharmaceutical composition according to claim 4, comprising a 2% w/w emulsifier blend. The pharmaceutical composition according to claim 1, comprising 10-30% w/w of diethylene glycol monoethyl ether. The pharmaceutical composition according to claim 7, comprising 25% w/w diethylene glycol monoethyl ether. The pharmaceutical composition according to claim 1, wherein the emulsifier blend is contained in an amount of 10% w/w, diethylene glycol monoethyl ether is contained in an amount of 25% w/w, and the pharmaceutical composition is a cream. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains 0.1 to 0.5% w/w of loflumilast, 2% w/w of an emulsifier blend, and 25% w/w of diethylene glycol monoethyl ether, and the pharmaceutical composition is a foamy substance.