Pharmaceutical compositions of roflumilast in aqueous blends of water-soluble pharmaceutically acceptable solvents

Abstract

The present application relates to pharmaceutical compositions of roflumilast in aqueous blends of water soluble pharmaceutically acceptable solvents. The low water solubility of roflumilast in parenteral formulations and topical emulsions, suspensions, gels, or solutions can be improved by a blend comprising a water-soluble solvent in a pharmaceutical composition. The blend of water soluble solvents may include diethylene glycol monoethyl ether (trade name # imgabs0 # abbreviated DEGEE) and water. The ratio of diethylene glycol monoethyl ether to water is 1: 10 to 20: 1. The resulting compositions have improved bioavailability and efficacy and are useful for inhibiting phosphodiesterase 4 in patients in need of such treatment.

Description

[0001] This application is a divisional application of Chinese patent application No. 201880060842.2, filed on September 19, 2018, with the invention name of “Pharmaceutical composition of roflumilast in an aqueous blend of a water-soluble pharmaceutically acceptable solvent”. Technical Field

[0002] The present invention relates to pharmaceutical compositions of Roflumilast in a blend of water-soluble pharmaceutically acceptable solvents. More specifically, the present invention relates to the discovery that Roflumilast, a poorly water-soluble drug, exhibits unexpectedly high solubility in such a blend of solvents. Background Art

[0003] Roflumilast is known to be suitable as a bronchial therapeutic agent and for the treatment of inflammatory diseases. Compositions containing Roflumilast are 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 diseases (e.g., bronchitis, asthma, COPD); skin diseases (e.g., proliferative, inflammatory and allergen-induced skin diseases), and generalized inflammation in the gastrointestinal region (Crohn's disease and ulcerative colitis).

[0004] Roflumilast and its synthesis are described in US Pat. No. 5,712,298 ("the '298 patent"), which is incorporated herein by reference (unless otherwise indicated, references cited herein are incorporated in their entirety for all purposes). It has long been recognized that pharmaceutical compounds with phosphodiesterase (PDE) inhibitory properties, such as roflumilast, can be used to treat psoriasis and atopic dermatitis (the '298 patent, column 11, lines 52-61), as well as other chronic inflammatory and allergen-induced skin diseases. For the treatment of such skin diseases, roflumilast emulsions, suspensions, gels or solutions for topical administration have been described (the '298 patent, column 12, lines 37-64). Although roflumilast oral tablets have been commercialized, the low water solubility of the compound at 21° C. of only 0.53 mg / l has been reported in WO 95 / 01338 (corresponding to the '298 patent and incorporated herein by reference). This low water solubility is problematic for the development of parenteral formulations and topical emulsions, suspensions, gels or aqueous solutions. In US 9,205,044 (incorporated herein by reference), the poor water solubility of Roflumilast was overcome by using alkoxylated fats, specifically polyoxyethylated 12-hydroxystearic acid, as a cosolvent for parenteral administration. In EP 1511516B1 (corresponding to published U.S. application Ser. No. 14 / 075,035, incorporated herein by reference), the low water solubility of Roflumilast in a topical emulsion (cream) formulation was overcome by formulating with polyethylene glycol 400 (PEG 400) at a concentration exceeding 62% (w / w) while maintaining the weight percentage of water below 10%.

[0005] It has been found that topical administration of effective pharmacological agents such as roflumilast for the treatment of skin diseases provides better delivery, lower systemic exposure and easier use for patients. The molecular structure of the compound ultimately determines the ability of the drug to pass through the epithelium of the tissue to which the product is applied. For skin application, the selection of formulation components determines the maximum skin permeability that the formulation designer can achieve. Creams, lotions, gels, ointments, foams and solutions are just some of the more familiar forms of topical roflumilast formulations, as disclosed in the '298 patent (column 12, lines 37-64), which generally contain a fully dissolved active pharmaceutical ingredient (API) for application to the skin. In order to treat such skin diseases, roflumilast emulsions, suspensions, gels or solutions have been documented for topical application, although the low solubility of the compound limits these applications.

[0006] Several methods for enhancing the solubility of active ingredients with low water solubility have been proposed. These methods include reducing particle size, hydrotrophic precipitation inhibitors (e.g., HPMC, PVP, PVA, PEG) complexation, solvent deposition, changing pH, freeze drying, surfactants, co-solvency, microemulsions, solid dispersions, and solvate formation. WO 2013 / 030789 discloses a PDE-IV inhibitor with poor water solubility and a binder selected from sugars (e.g., sucrose, lactose, microcrystalline cellulose, low viscosity hydroxypropyl cellulose and / or hydroxypropyl methylcellulose), proteins (e.g., gelatin), or synthetic polymers (e.g., polyethylene glycol, polyvinyl acetate, polyvinyl alcohol, and propylene glycol). In US 9,205,044 (cited herein), the poor water solubility of Roflumilast is overcome by using alkoxylated fats, specifically polyoxyethylated 12-hydroxystearic acid as a cosolvent. In EP 1511516B1 (corresponding to the disclosed U.S. application Ser. No. 14 / 075,035, incorporated herein by reference), the low water solubility of roflumilast in a topical emulsion (cream) formulation is overcome by formulating with polyethylene glycol 400 (PEG 400) at a concentration exceeding 62% (w / w) while maintaining the weight percentage of water below 10%. U.S. Pat. No. 7,951,398 (incorporated herein by reference) discloses a solid dispersion of roflumilast, which is indicated as a poorly soluble drug, wherein roflumilast is dispersed in a matrix comprising fatty alcohols, triglycerides, and fatty acid esters at elevated temperatures, then cooled and granulated with a hydrophilic polymer. U.S. Pat. No. 6,074,670 discloses a composition of fenofibrate, which is a poorly soluble drug, having improved solubility. The composition comprises a hydrophilic polymer and a surfactant, wherein fenofibrate is granulated with a solution of a hydrophilic polymer (e.g., polyvinyl pyrrolidone), which results in an improved dissolution profile. U.S. Patent No. 8,431,154 (incorporated herein by reference) discloses a composition of roflumilast with improved release and improved pharmacokinetic properties by granulating roflumilast using an aqueous solution of polyvinyl pyrrolidone (PVP) by preparing a solid solution or solid dispersion. Published U.S. Application Serial No. 14 / 114,541 (incorporated herein by reference) discloses that a novel PI3K inhibitor can be combined with a soluble macromolecular entity (e.g., cyclodextrin and a suitable derivative thereof or a polymer containing polyethylene glycol) to improve its solubility, dissolution rate, taste masking, bioavailability, and / or stability.

[0007] WO 2015 / 132708 discloses the use of a multi-particulate composition comprising roflumilast and an inert component. The inert component is prepared by granulation and then mixed with roflumilast to obtain a composition with improved dissolution. The composition preferably comprises polyvinyl alcohol as part of the inert component.

[0008] One technique for increasing the solubility of an active ingredient is to blend an alcohol or glycol with water to produce a solvent blend that is less polar than water. Since pharmaceutically acceptable alcohols (e.g., ethanol or isopropanol) are not ideal excipients for topical application to inflammatory skin conditions (because they tend to further irritate the inflamed skin), propylene glycol is a commonly used cosolvent in topical creams and gels used to treat psoriasis or atopic dermatitis. Propylene glycol (abbreviated as PG) has been used to increase the solubility of corticosteroids in topical gels, lotions, and creams that often contain greater than 20% water and volatiles and / or less than 50% hydrocarbons, waxes, or polyols (USP 5000). <1151> Definition of topical emulsion). Another solvent that is chemically very similar to PG and was first used in an FDA-approved topical product in 2005 is diethylene glycol monoethyl ether (trade name ), and abbreviated as DEGEE. Diethylene glycol monoethyl ether is used as a carrier and as a solubilizer in the preparation of pharmaceutical compositions (see, for example, U.S. application serial numbers 14 / 242,973; 12 / 846079 and 15 / 376,345, incorporated herein by reference). Diethylene glycol monoethyl ether is also used as a skin permeability enhancer (U.S. application serial numbers 15 / 260,554 and 15 / 297,998, incorporated herein by reference) and a surfactant (U.S. 9,649,302, incorporated herein by reference). Although PG has been used in many FDA-approved topical products for decades longer than DEGEE, the two solvents are very similar, as shown in Table 1. However, these solvents have different effects on the solubility and skin permeability of different active ingredients.

[0009] Table 1. Comparison of two pharmaceutically acceptable glycols for topical products.

[0010]

[0011]

[0012] Minghetti et al. (J. Pharm. Sci. 96 (4) 814-823, 2007) determined the solubility of four salts of diclofenac in pure PG and pure DEGEE, and the solubility data are summarized in Table 2. Table 2. Solubility data of four salts of diclofenac, taken from P. Minghetti et al., J. Pharm. Sci 96 ,814-823)

[0013]

[0014] Although both solvents are considered safe for topical application up to and exceeding about 50 weight percent, pharmaceutical formulations typically limit the amount of DEGEE or PG to about 30% due to irritation observed in a subset of patients. Therefore, these diols are almost always blended with water when formulating topical gels or emulsions (creams or lotions). When two solvents are blended, the ideal solubility of any blend can be calculated based on the solubility of the active ingredient in each individual solvent. When the physical properties of the two solvents are closely aligned, the calculated "ideal" solubility will be most consistent with the observed solubility. JW Lorimer's publication on the thermodynamics of solubility in mixed solvent systems (Pure & Appl. Chem. 65 (2) 183-191, 1993) showed an accurate correlation between the ideal and measured solubility of NaCl when dissolved in a blend of water (H2O) and deuterium oxide (D2O), as well as reasonable correlation of the data for NaCl in a blend of water and ethylene glycol. For the blend of water and ethylene glycol, the worst correlation between the calculated "ideal" solubility and the observed solubility occurred in an equimolar mixture of the two solvents, with the observed saturation solubility being 18 times lower than the calculated ideal solubility (J. Solution Chem., 14 , 635 (1985)). Lorimer used classical thermodynamics to derive the ideal solubility (shown in the article as ln(m s (12) / m o ).

[0015] The ability to calculate the expected solubility at any ratio of a solvent blend after experimentally determining the drug solubility in each of two pure solvents aids in the formulation of topical products. Typically, the target concentration has been determined based on the potency of the API. Highly potent pharmaceutical active ingredients (such as some corticosteroids or calcipotriol) have a target concentration in a topical product of 0.05% to 0.5%. Most topical products will be around 2%. Since the maximum thermodynamic driving force across the skin occurs at saturation, a skilled formulation designer would like to know the saturated drug concentration in a solvent blend at a range of solvent blend ratios. By calculating the ideal solubility values ​​before building a full matrix of experimental solubility determinations, the number of experiments to observe saturated drug solubility determinations can be reduced from hundreds to less than 100. Summary of the invention

[0016] According to the present invention, it has been found that surprisingly high concentrations of Roflumilast can be dissolved in a solvent blend of diethylene glycol monoethyl ether (DEGEE) and water. When the solvent blend is formulated with up to 0.5% of Roflumilast in a moisturizer, the significantly enhanced solubility of Roflumilast is maintained. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The patent or application file contains at least one image executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0018] Figure 1 Shown is a micrograph of a sample of Formulation 1 using a polarized light microscope equipped with a 10X objective.

[0019] Figure 2 Shown is a micrograph of a sample of Formulation 2 using a polarized light microscope equipped with a 10X objective.

[0020] Figure 3 Micrographs of samples of Formulation 3 using a polarized light microscope equipped with a 10X objective are shown. The blue arrows point out the five largest undissolved roflumilast particles in the micrographs of these five creams.

[0021] Figure 4 Micrographs of samples of Formulation 4 using a polarized light microscope equipped with a 10X objective are shown. The blue arrows point out the five largest undissolved roflumilast particles in the micrographs of these five creams.

[0022] Figure 5 Micrographs of samples of Formulation 5 using a polarized light microscope equipped with a 10X objective are shown. The blue arrows point out the five largest undissolved roflumilast particles in the micrographs of these five creams. DETAILED DESCRIPTION

[0023] Roflumilast is a compound of formula (I):

[0024]

[0025] wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3 is 3,5-dichloropyridin-4-yl.

[0026] The chemical name of this compound is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: Roflumilast). Roflumilast can be prepared by methods known in the art (eg, see the '298 patent and US Application No. 14 / 075,035).

[0027] Diethylene glycol monoethyl ether is a compound of formula (II)

[0028]

[0029] The present invention relates to a method of dissolving roflumilast in diethylene glycol monoethyl ether (DEGEE, Gattefosse trade name) ) and water, optionally comprising one or more pharmaceutically acceptable carriers. Any suitable grade of include P. HP, V and This blend of CG.DEGEE and water can be added with excipients and further processed to form a range of pharmaceutical dosage forms and maintain dissolved or molecularly dispersed Roflumilast during the shelf life of the drug product.

[0030] The present invention is particularly useful for topical formulations. Topical roflumilast drug product formulations based on DEGEE-water blends may be described in the United States Pharmacopeia (USP) <1151> The term "aerosol" is defined in the Table of Contents and includes aerosols, foams, sprays, emulsions (which may also be referred to as creams, lotions or ointments), gels (two-phase or single-phase), liquids, ointments, pastes, shampoos, suspensions and systems. These are typical dosage forms containing pharmaceutical active ingredients for topical administration to mammals, including humans.

[0031] Topical administration refers to administration to the skin, hair or nails of a patient who would benefit from treatment with a pharmaceutical product. Topical can also mean application to the patient's epithelium for local delivery. This includes administration of Roflumilast via the eye, ear, oral mucosa, vaginal mucosa, rectal mucosa or urethra. The broadest definition of topical would include using the patient's epithelium as a route of administration to obtain therapeutic systemic levels of active ingredients. This definition of topical is commonly referred to as transdermal delivery of therapeutic active ingredients.

[0032] In topical preparations, DEGEE is often formulated at 10-30% (w / w), preferably 15-20% (w / w). Similarly, water is formulated at about 20-90% (w / w) in topical products. For blends of DEGEE and water, the ratio ranges from 1:10 to 20:1. In formulations containing roflumilast, the ratio of DEGEE:water is preferably 1:4 to 9:1.

[0033] Typically, the DEGEE-water blend can be used to dissolve up to 2.0% of Roflumilast (in the finished product) or preferably up to 0.5% of Roflumilast (in the finished product). The finished product is preferably in one of the following forms:

[0034] Oil-in-water emulsions: The topical products may be emulsions comprising a dispersed hydrophobic phase and a continuous aqueous phase comprising a DEGEE-water blend and optionally one or more polar hydrophilic excipients, as well as solvents, cosolvents, salts, surfactants, emulsifiers and other components. These emulsions may contain water-soluble or water-swellable polymers that help stabilize the emulsion.

[0035] Water-in-oil emulsions: The compositions may be formulations in which Roflumilast is incorporated into an emulsion comprising a continuous hydrophobic phase and an aqueous phase comprising a DEGEE-water blend and optionally one or more polar hydrophilic carriers, as well as salts or other components. These emulsions may contain an oil-soluble or oil-swellable polymer and one or more emulsifiers that help stabilize the emulsion.

[0036] For oil-in-water emulsions and water-in-oil emulsions, the order of addition may be important. Roflumilast pre-dissolved in a continuous aqueous phase containing a DEGEE-water blend can be added. Similarly, Roflumilast can be pre-dissolved in the hydrophobic dispersed phase of the emulsion and then mixed with a DEGEE-water blend not containing an active ingredient and an optional hydrophilic excipient. Roflumilast can be pre-dissolved in the oil phase and the aqueous phase of the emulsion, or Roflumilast pre-dissolved in DEGEE or a DEGEE-water blend can be added after the emulsion is formed. During the cooling of the emulsion, some emulsions undergo phase transitions within a specific temperature range. Therefore, Roflumilast can be added to a water-in-oil emulsion above the phase transition temperature, and the final drug product is an oil-in-water emulsion at controlled room temperature, and vice versa.

[0037] Thickened aqueous gels: These systems comprise a DEGEE-water blend with dissolved Roflumilast and optionally one or more polar hydrophilic carriers (such as hexylene glycol) thickened by a suitable natural, modified natural or synthetic thickener as described below. Alternatively, the thickened aqueous gels may be thickened using suitable polyethoxylated alkyl chain surfactants or other nonionic, cationic or anionic systems.

[0038] Thickened hydroalcoholic gels: These systems contain a DEGEE-water-alcohol blend with dissolved Roflumilast and optionally one or more polar hydrophilic carriers (such as hexylene glycol) as the polar phase, which has been thickened by a suitable natural, modified natural or synthetic polymer as described below. Alternatively, the thickened hydroalcoholic gels may be thickened using suitable polyethoxylated alkyl chain surfactants or other nonionic, cationic or anionic systems. The alcohol may be ethanol, isopropanol or other pharmaceutically acceptable alcohols.

[0039] Hydrophilic or hydrophobic ointment: The composition is formulated with a hydrophobic base (e.g., petrolatum, thickened or gelled water-insoluble oils, etc.), and optionally with a small amount of DEGEE-water blend with dissolved roflumilast. Hydrophilic ointments typically contain one or more surfactants or wetting agents.

[0040] Solvents

[0041] The compositions of the present invention may contain one or more solvents or cosolvents to obtain the desired level of solubility of the active ingredient in the product. The solvents may also alter the activity of other excipients contained in the skin permeation or topical product. Solvents include, but are not limited to, acetone, ethanol, benzyl alcohol, butanol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isostearate, isopropyl myristate, N-methylpyrrolidone, propylene glycol, and SD alcohol.

[0042] Moisturizer

[0043] The compositions of the present invention may include a humectant to increase the level of hydration. For emulsions, the humectant is typically a component of a dispersed or continuous hydrophobic phase. The humectant may be a hydrophilic material including a humectant, or it may be a hydrophobic material including an emollient. Suitable moisturizers include, but are not limited to, 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, behenyl alcohol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, ethylene glycol distearate, ethylene 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.

[0044] Surfactants and emulsifiers

[0045] The compositions of the present invention may optionally include one or more surfactants to emulsify the composition and aid in wetting the surface of the active ingredient or excipient. As used herein, the term "surfactant" refers to an amphiphilic molecule (a molecule having both covalently bound polar and non-polar regions) that is capable of reducing the surface tension of water and / or the interfacial tension between water and an immiscible liquid.Surfactants include, but are not limited to, sodium alkylaryl sulfonate, Amerchol-CAB, ammonium lauryl sulfate, almond oil PEG-6 esters, Arlacel, benzalkonium chloride, ceteareth-6, ceteareth-12, ceteareth-15, ceteareth-30, cetearyl alcohol / ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-10 phosphate, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide ether sulfate, cocoamine oxide, coco-sweetened Betaine, Cocoyl Diethanolamine, Cocoyl Monoethanolamine, Coco Caprylate / Coco Caprate, Dicetyl Phosphate, Disodium Cocoamphodiacetate, Disodium Laureth Sulfosuccinate, Disodium Laureth Sulfosuccinate, Disodium Laureth Sulfosuccinate, Disodium Oleamido Monoethanolamine Sulfosuccinate, Sodium Docusate, Laureth-2, Laureth-23, Laureth-4, Lauroyl Diethanolamine, Lecithin, Methoxy PEG-16, Methyl Gluceth-10, Methyl Gluceth-20, Methyl Glucose Sesquistearate, Oleth-2, Oleth-20, PEG 6-32 Stearate, PEG-100 Stearate, PEG-12 Lauric Glyceryl, PEG-120 Methyl Glucose Dioleate, PEG-15 Cocoamine, 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, Pentaerythrityl Cocoate, Poloxamer 124, Poloxamer 181, Poloxamer 182, Poloxamer 188, Poloxamer 237, Poloxamer 407, Polyglyceryl-3 Oleate, Polyoxyethylene Alcohol, Polyoxyethylene Fatty Acid Esters, Polyoxyethylene 20 Cetearyl Ether, Polyoxyethylene 40 Hydrogenated Castor Oil, Polyoxyethylene 40 Stearate, Polyoxyethylene 6 and Polyoxyethylene 32, Polyoxyethylene Stearic Acid Glyceryl, Polyoxyethylene Stearate, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80, PPG-26 Oleate, PROMULGEN. TM12. 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, tallow glycerides and emulsifying wax.

[0046] Polymers and Thickeners

[0047] For certain applications, it may be desirable to formulate topical products thickened with soluble, swellable or insoluble organic polymer thickeners such as natural and synthetic polymers or inorganic thickeners, including but not limited to acrylate copolymers, carbomer 1382, carbomer type B copolymers, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxyvinyl copolymers, carboxymethylcellulose, carbopol, carrageenan, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline wax and methylcellulose.

[0048] Additional components

[0049] The composition of the present invention can be formulated with the additional components conventionally present in cosmetic and pharmaceutical topical products. Additional components include, but are not limited to, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulating solutions, transdermal absorption enhancers, film-forming materials, dyes, pigments, fragrances and other excipients that improve the stability or aesthetics of the product. In a preferred embodiment, hexylene glycol is added to suppress the change of particle size distribution during the shelf life of the composition. Hexylene glycol can be added 0.1% to 20% by weight / weight, preferably 0.25% to 8% by weight / weight, and most preferably 0.5% to 2% by weight / weight.

[0050] The composition of the present invention can be formulated with additional active agents according to the condition to be treated. The additional active agents include, but are not limited to, anthralin (anthraquinone), azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarate, corticosteroids (e.g., alclometasone, amcinonide, betamethasone, clobetasol, clocotolone, mometasone, triamcinolone, fluocinolone acetonide, flurandrenolide, flurandrenolide, , diflorasone, desonide, desoximetasone, dexamethasone, halcinonide, ubetasol, hydrocortisone, methylprednisolone, prednicarbate, prednisone), adrenocorticotropic hormone, vitamin D analogs (e.g., calcipotriol, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, colchicine, adalimumab, ustekinumab, infliximab, bronchodilators (e.g., beta-agonists, anticholinergics, theophylline), and antibiotics (e.g., erythromycin, ciprofloxacin, metronidazole).

[0051] Administration and Dosage

[0052] The compositions of 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, atomization, skin (topical), transdermal and mucosal (e.g., sublingual, buccal, nasal). In a preferred embodiment, the composition is administered topically.

[0053] Suitable pharmaceutical dosage forms include, but are not limited to, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels, foams, transdermal patches, and solutions (eg, injectable, oral).

[0054] The composition preferably contains roflumilast, a salt of roflumilast, roflumilast N-oxide or a salt thereof in an amount of 0.005-2% w / w, more preferably 0.05-1% w / w, and most preferably 0.1-0.5% w / w per dosage unit.

[0055] The composition preferably contains diethylene glycol monoethyl ether in an amount of 5% to 50% w / w, more preferably 20% to 30% w / w, and most preferably 22.5% to 27.5% w / w.

[0056] The composition may be administered once or more times a day, preferably the composition is administered 1-2 times a day.

[0057] The composition can be used in veterinary and human medicine for the treatment and prevention of all diseases that are considered treatable or preventable by the use of roflumilast, including but not limited to acute and chronic airway diseases; proliferative, inflammatory and allergic skin diseases; diseases based on excessive release of TNF and leukotrienes; heart diseases that can be treated with PDE inhibitors; inflammation in the gastrointestinal system or the central nervous system; eye diseases; arthritic diseases; and diseases that can be treated by the tissue relaxation effect of PDE inhibitors. 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.

[0058] The following examples are provided to enable one of ordinary skill 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 the invention. Other advantages and modifications will be apparent to those skilled in the art.

[0059] Example 1

[0060] 0.0061 grams of Roflumilast (Batch A14367P from Interquim SA) was weighed into a liquid scintillation vial. PG (propylene glycol, Spectrum Chemical batch IEC0004) was added dropwise to the vial containing Roflumilast under mixing. After each addition of PG was mixed, the tightly capped vial was returned to a water bath set at 25°C. It takes 1.9332 grams of PG to completely dissolve 0.0061 grams of Roflumilast, which is equivalent to an observed saturated solubility of 0.3 w / w% of Roflumilast in PG at 25°C. The value of 0.53 mg / l (at 21°C) described in WO95 / 01338 was used as the observed value of the saturated solubility of Roflumilast in water, which is equal to 0.000053 w / w%. Using the Lorimer equation, the observed saturation solubility in PG (0.3% Roflumilast), and the observed saturation solubility in water (0.000053%), the calculated ideal solubility of Roflumilast in equimolar PG:water is 0.0040 w / w%.

[0061] An equimolar blend of 2.3200 grams of PG (Spectrum Chemical batch IEC0004) and distilled water was prepared and added to a scintillation vial containing 0.0012 croflumastat (batch A14367P from Interquim SA). After equilibration to 25°C, the roflumilast was completely dissolved to form a 0.052% solution. On a weight / weight percentage basis, the equimolar blend was 80.7% PG and 19.3% water. The addition of 2.2696 grams of equimolar PG:water at 25°C did not completely dissolve 0.0017 croflumastat (0.075% roflumilast). The experimentally determined observed saturated solubility of roflumilast equimolar PG:water at 25°C was 0.06 w / w%.

[0062] The observed saturated solubility of Roflumilast in equimolar PG:water at 25°C was 15-fold higher than the calculated ideal solubility of Roflumilast in an equimolar PG:water blend (80.7:19.3 PG:water w / w).

[0063] Example 2

[0064] 0.0205 grams of Roflumilast (Batch A14367P from Interquim SA) was weighed into a liquid scintillation vial. DEGEE (Transcutol P, batch number 146063, Gattefosse) was added dropwise to the vial containing Roflumilast under mixing. After each addition of DEGEE was mixed, the tightly capped vial was returned to a water bath set at 25°C. It takes 0.2699 grams of DEGEE to completely dissolve 0.0205 grams of Roflumilast, which is equal to the observed saturated solubility of 7.1w / w% of Roflumilast in DEGEE at 25°C. The value 0.53mg / l (at 21°C) described in WO95 / 01338 was used as the observed value of the saturated solubility of Roflumilast in water, which is equal to 0.000053w / w%. Using the Lorimer equation, the observed saturation solubility in DEGEE (7.1% Roflumilast), and the observed saturation solubility in water (0.000053%), the calculated ideal solubility of Roflumilast in equimolar DEGEE:water is 0.019 w / w%.

[0065] 0.0111 grams of Roflumilast (Batch A14367P from Interquim SA) was weighed into a liquid scintillation vial. An equimolar blend of DEGEE (Transcutol P, batch 146063, Gattefosse) and distilled water was prepared and added dropwise to the vial containing Roflumilast under mixing. The equimolar blend was 88.3% DEGEE and 11.7% water by weight / weight percentage. After mixing each equimolar DEGEE: water addition, the tightly capped vial was returned to a water bath set at 25°C. 0.0111 grams of Roflumilast did not dissolve after adding 0.2337 grams of equimolar DEGEE: water (4.53% Roflumilast), but dissolved after adding 0.2477 grams of equimolar DEGEE: water (4.29% Roflumilast). The experimentally determined saturated solubility of roflumilast in equimolar DEGEE:water at 25°C was 4.4 w / w%.

[0066] The observed saturated solubility of Roflumilast in equimolar DEGEE:water at 25°C was 232-fold higher than the calculated ideal solubility of Roflumilast in an equimolar DEGEE:water blend (88.3:11.7 DEGEE:water w / w).

[0067] Example 3

[0068] 0.5% roflumilast cream was prepared according to the following recipe. After storage in a sealed glass container for at least one month, a thin smear of the cream was placed on a glass microscope slide and a cover slip was placed on the sample. Micrographs of the samples were obtained using a polarized light microscope equipped with a 10X objective ( Figure 1-5 ). The micrographs were examined to determine if undissolved Roflumilast was present in the creams. The blue arrows point to the five largest undissolved Roflumilast particles in the micrographs of the five creams. Only the two creams containing Transcutol (25%) contained no undissolved active agent.

[0069] Preparation 1

[0070]

[0071] *(Trade name for Croda emulsifier blend of cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate)

[0072] Preparation 2

[0073]

[0074] Preparation 3

[0075]

[0076] **(Trade name for BASF emulsifier blend of Ceteareth-6 and Stearyl Alcohol)

[0077] Preparation 4

[0078]

[0079]

[0080] ***(Trade name for Croda Emulsifier PEG-75 Lanolin)

[0081] Preparation 5

[0082]

Claims

1. A method for overcoming the low water solubility of a Roflumilast composition, comprising adding diethylene glycol monoethyl ether and water to the Roflumilast composition, wherein the amount of roflumilast is 0.05-2% (w / w), the amount of diethylene glycol monoethyl ether is 15-25% (w / w), and the amount of water is 20-90% (w / w), wherein the roflumilast is at a saturation concentration, and The pharmaceutical composition is a cream or a foam.

2. The method of claim 1, wherein the Roflumilast composition comprises 0.1-0.5% (w / w) Roflumilast.

3. Use of a composition for preparing a medicament for inhibiting phosphodiesterase 4 in a patient, wherein the composition comprises 0.05-2% (w / w) of roflumilast, 15-25% (w / w) of diethylene glycol monoethyl ether and 20-90% (w / w) of water.

4. The use according to claim 3, wherein the medicament is for treating inflammatory disorders.

5. The use according to claim 4, wherein the medicament is used to treat atopic dermatitis.

6. The use of claim 3, wherein the roflumilast is present in an amount of 0.05-0.5% (w / w).

7. The use of claim 3, wherein the roflumilast is present in an amount of 0.1-0.5% (w / w).

8. The use of claim 3, wherein the medicament further comprises hexylene glycol in an amount of 0.1-20% (w / w).

9. The use according to claim 8, wherein the medicament further comprises hexylene glycol in an amount of 0.25-8% (w / w).

10. The use according to claim 9, wherein the medicament further comprises hexylene glycol in an amount of 0.5-2% (w / w).

11. The use of claim 4, wherein the medicament is for treating psoriasis.

12. The method of claim 1, wherein the Roflumilast composition comprises 0.05-0.5% (w / w) Roflumilast.

13. The method of claim 1, wherein the roflumilast composition is suitable for topical administration.

14. The method of claim 1, wherein the roflumilast composition is a cream.

15. The method of claim 1, wherein the roflumilast composition further comprises hexylene glycol in an amount of 0.1-20% (w / w).

16. The method of claim 1, wherein the roflumilast composition further comprises hexylene glycol in an amount of 0.25-8% (w / w).

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