Method and preparation for improving lagging time of skin penetration of roflumilast

Abstract

Reducing the skin penetration lag time improves the bioavailability of the locally administered roflumilast composition. The shorter skin penetration lag time provides faster disease relief and more sustained bioavailability because there is less opportunity to transfer to clothes or others. The skin penetration lag time of roflumilast can be reduced by formulating a roflumilast composition to have a pH of 4.0 to 6.5 and / or mixing roflumilast with an emulsifier blend comprising cetostearyl alcohol, a dicetyl phosphate, and a ceteth-10 phosphate ester.

Description

[0001] This application is a divisional application of Chinese patent application 201980046472.1, filed on May 30, 2019, entitled “Methods and preparations for improving the lag time of skin penetration of roflumilast”. Background of the Invention

[0002] Pharmacokinetics is the study of the movement of a drug through a patient's body over time. There are four phases used to determine the pharmacokinetics of a drug, namely absorption, distribution, metabolism, and excretion. Absorption following topical administration is the movement of a drug from the site of administration across one or more cell membrane barriers into the circulation. Absorption of topically administered drugs is important for dermatological treatments and for topical administration of systemic drugs. After topical administration, the drug must first be absorbed into the skin. Drug metabolism may occur in the skin, or the drug may enter the systemic circulation before metabolism. Once a topically administered drug reaches the systemic circulation, its fate is similar to that of a systemically administered drug. The concentration of drug that reaches the target site after topical administration depends largely on the properties of the drug itself and its formulation, as well as the properties of the patient's skin.

[0003] Healthy skin, either in pigs or humans, absorbs the active pharmaceutical ingredient from a topically applied semisolid in a very predictable manner. After initial skin exposure to the compound, the cumulative influx into the skin follows Figure 1 The time course shown in (a) and the efflux of the same compound into the vasculature are shown Figure 1Time course shown in (b). The influx rate starts at a higher rate because there is initially no compound in the skin, or more precisely, no drug in the intercellular spaces of the stratum corneum. The higher influx rate is due to the fact that the drug concentration in the non-volatile product is at its highest concentration at the initial administration of the topical semisolid, resulting in a maximum thermodynamic driving force for drug influx into the skin. At this point, efflux into the vasculature is negligible. Robinson defines the "lag time" in this way (PJ Robinson, "Prediction—Simple Risk Models and Overview of Dermal Risk Assessment", Dermal Absorption and toxicity Assessment, Chapter 8, pages 203-229, edited by Michael S. Roberts and Kenneth A. Walters, Marcel Dekker, New York, 1998, page 215): "After a period of time, the drug accumulates in the skin, and the efflux into the blood increases. Eventually, enough material has accumulated in the skin itself that a steady state is reached, in which the influx into the skin equals the efflux from the skin into the vasculature. After such a "lag time" (which depends on the compound and can be an hour or more), curves (a) and (b) have the same slope (dominated by the skin permeability coefficient, K). p It should be noted that the total amount of drug entering the skin (influx) is always greater than the amount of drug entering the vasculature (efflux). In other words, Figure 1 Curve (a) in the figure is always above curve (b). Mathematically, the skin permeability coefficient Kp can be solved using Fick's diffusion law derived by Adolf Fick in 1855.

[0004] For clinically relevant administration of limited amounts of topical semisolids applied to affected skin, the cumulative influx of active substance into the skin ( Figure 2 a) and outflow into the vascular system ( Figure 2b) will be significantly different in time course. Due to the limited duration of exposure to the compound, a plateau will appear in the time course curve for influx into the skin and a corresponding plateau will appear in the curve for outflow into the vasculature. For a single dose application, the two plateau lines will eventually become parallel with a difference in amplitude representing the percentage of the applied dose absorbed. In practice, when a patient's skin disease is treated topically, a second dose is administered before the cumulative skin influx curve and the cumulative vascular outflow curve become truly parallel. However, there are two aspects of how topically applied pharmaceutical active ingredients penetrate the skin that are strictly followed: 1) there is a lag time between influx into the skin and outflow into the vasculature, and 2) the amount of drug that enters the skin is always greater than the amount of drug that enters the vasculature. These two rules apply to ex vivo, in vitro, or in vivo administration to humans or mammals using clinically relevant finite dosing or unlimited dosing used in in vitro membrane diffusion experiments.

[0005] To better understand the first aspect of topical skin penetration described above, it should be noted that the lag time between influx into the skin and efflux into the vasculature measured using an in vitro permeation test (IVPT) can be greatly shortened compared to the lag time for the active substance to reach measurable blood concentrations in pharmacokinetic (PK) studies. For IVPT, excised human skin is cut to a depth of 200-600 microns to ensure that the stratum corneum and skin barrier are intact, but the lower dermis located below the skin vasculature network, which removes the active substance from the skin, i.e., vascular outflow, is cut away. The skin is cut using a dermatome and mounted on a diffusion cell that allows the formulation to be administered to the stratum corneum and the receptor solution in contact with the dermal cut surface to be sampled. The time point at which a measurable concentration of the active ingredient appears in the receptor solution can be inferred to calculate the lag time, assuming that the time course of passive diffusion through the stratum corneum, epidermis, and upper dermis is similar for the excised skin and the intact skin of the individual to whom the topical drug is administered. For PK research, once the active substance enters the vascular system and the skin outflow begins, multiple mechanisms will dilute or remove the active substance in the blood to a concentration below the detection limit of the bioanalytical method. Since PK sampling is completed away from the site where the topical product is applied (dosage on the back, but blood is drawn from the arm), the initial outflow is diluted by the blood volume of the individual (mammal or human) being studied. The drug that flows out from the skin to the vascular system will then be distributed to the tissue, and the metabolism and excretion characteristics of the drug further delay the detection in the blood and extend the lag time. These PK parameters (such as distribution volume and drug half-life) are characterized using the intravenous administration amount of the drug, and compared with the results after topical administration, to determine the skin bioavailability of the topical dermatological preparation (MSRoberts and KAWalters, "The Relationship Between Structure and Barrier Function of Skin", Dermal Absorption and toxicity Assessment, Chapter 1, Pages 1-42, edited by Michael S.Roberts and Kenneth A.Walters., Marcel Dekker, New York, 1998, Page 21). Therefore, lag times measured using IVPT are shorter than those measured in PK experiments because the time required to reach measurable blood levels of the active substance is always longer than the time it takes for the active substance to diffuse to the skin depth required to reach the vasculature to exit the skin.

[0006] As described above in the Robinson reference, it is well known that lag time depends on the compound penetrating the skin and can be an hour or longer. It is well known that combining skin penetration enhancers (Osborne & Henke reference), excipients with pharmaceutical active ingredients to formulate topical products can affect lag time and increase the amount of active ingredient that passes through the stratum corneum. Therefore, scientists developing topical drug products typically use IVPT to screen multiple prototype formulations to select which final composition can enter the non-clinical and clinical studies required to advance dermatological products through the approval process. During the development of topical roflumilast for the treatment of inflammatory skin diseases, it was discovered that the lag time of roflumilast dissolved in a topical formulation containing an emulsifier (wherein the formulation has a pH of 4.0-6.5) was surprisingly short, less than 1 hour, when applied to a living mammal.

[0007] Roflumilast and its synthesis are described in US Pat. No. 5,712,298 ("the '298 patent"), which is incorporated herein by reference (* all references incorporated herein by reference are incorporated by reference in their entirety for all purposes unless otherwise indicated). It has long been recognized that pharmaceutical compounds such as roflumilast with phosphodiesterase (PDE) inhibitory properties are useful for treating psoriasis and atopic dermatitis (the '298 patent, col. 11, lines 52-61) and other chronic inflammatory skin diseases and allergen-induced skin diseases. To treat such skin diseases, roflumilast emulsions, suspensions, gels or solutions for topical administration have been described (the '298 patent, col. 12, lines 37-64).

[0008] It has been found that topical administration of potent agents for the treatment of skin diseases such as roflumilast provides patients with superior delivery, lower systemic exposure and greater ease of use. The molecular structure of the compound ultimately determines the ability of the drug to penetrate the tissue epithelium to which the product is applied. For topical administration to the skin, the choice of formulation ingredients determines the maximum skin penetration that the formulator can achieve. Creams, lotions, gels, ointments and foams are just a few of the more familiar forms of topical products containing active pharmaceutical ingredients (API) for application to the skin.

[0009] 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 an active penetrates the skin (JD Bos, MM Meinardi, Exp Dermatol. 2000 Jun; 9(3): 165-9). Another well-known relationship is that increasing the octanol-water partition coefficient of a hydrophilic active initially increases the rate at which the active penetrates the skin, but decreases skin permeability once the active becomes too lipophilic to separate from the stratum corneum and enter the subepidermal layers (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 typically a logP value of 2-3. The rate at which an active ingredient enters the viable epidermis can be further modified based on the composition of the topical product. The final pH of the formulation can be critical because dissolved ionized active ingredients generally do not penetrate the skin as effectively as uncharged active ingredients (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. For active substances dissolved in topical products, 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 to pass through the skin, that is, the greater the skin flux of the active substance. The scientific literature guides formulators how to increase penetration through polar pathways, non-polar pathways, and intercellular lipid pathways or transfollicular permeation.

[0010] Methods to reduce the skin penetration lag time would improve the bioavailability of topically administered roflumilast, thereby improving the therapeutic outcome of topically treated skin diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Shown is a comparison of the ideal influx curve (a) and the flux curve (b) following infinite dosing (adapted from Robinson).

[0012] Figure 2 Shown is a comparison of the ideal influx curve (a) and the flux curve (b) after finite drug administration.

[0013] Figure 3Five creams containing Crodafos CES as an emulsifier were shown to have measurable levels of roflumilast in the receptor solution one hour after administration. These creams had essentially the same extrapolated lag time of 50-60 minutes, and when their pH was adjusted to 5.0 to 6.5, the lag time was slightly less than 1 hour. SUMMARY OF THE INVENTION

[0014] According to the present invention, it was found that maintaining the pH of the topically administered Roflumilast at a pH of 4.0-6.5 and / or combining Roflumilast with a specific emulsifier resulted in a skin penetration lag time of less than one hour. This surprisingly short lag time is particularly important in the topical treatment of inflammatory skin diseases because it not only provides faster disease relief, but also because Roflumilast stays on the skin surface for a shorter time and is not easily transferred to clothing or other people, so the bioavailability of the active substance is more constant. DETAILED DESCRIPTION OF THE INVENTION

[0015] Roflumilast is a compound of formula (I)

[0016]

[0017] wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyridin-4-yl.

[0018] 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 Patent Application No. 14 / 075,035).

[0019] Diethylene glycol monoethyl ether is a compound of formula (II)

[0020]

[0021] Produced by Croda under the trade name CRODAFOS TM An emulsifier blend of CES cetearyl alcohol (CAS 6776230 0), dicetyl phosphate (CAS 2197 63 9) and ceteth-10 phosphate (CAS 50643-20-4). This commercially available emulsifier blend is a self-emulsifying wax, which is mainly composed of the waxy substance cetearyl alcohol (Cetyl alcohol (C 16 H 34 O) and stearyl alcohol (C 18 H 38O) in combination with 10-20% dicetyl phosphate and 10-20% ceteth-10 phosphate. When mixed with water, the self-emulsifying wax forms an emulsion. When CRODAFOS TM After CES is added to water, it spontaneously forms an emulsion with a pH of approximately 3. Sodium hydroxide solution is added to increase the pH to the desired value.

[0022]

[0023] Ceteth-10 Phosphate

[0024] The present invention relates to a pharmaceutical composition of roflumilast, wherein the pH value of the composition is adjusted to 4.0-6.5. In a preferred embodiment, roflumilast can be mixed with diethylene glycol monoethyl ether (DEGEE, Gattefosse trade name ) and water. The pH-adjusted aqueous DEGEE blend optionally contains one or more pharmaceutically acceptable carriers. Any suitable grade of can be used, including and This blend of DEGEE and water can be added to excipients and further processed to form a range of pharmaceutical dosage forms and maintain dissolved or molecularly dispersed Roflumilast over the shelf life of the drug product. In another embodiment, hexylene glycol can be included in the Roflumilast composition.

[0025] The present invention also relates to a self-emulsifying wax blend of roflumilast and cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate (Croda trade name CRODAFOS TM The pharmaceutical composition is a mixture of CRODAFOS (CES) and water, the pH of which is adjusted to 4.0-6.5. The pH-adjusted aqueous phosphate-based emulsifying wax optionally contains one or more pharmaceutically acceptable carriers. Any suitable grade of CRODAFOS TM , including CRODAFOS TM CES-PA and CRODAFOS TM CS20A. This blend of phosphate ester self-emulsifying wax and water can be added to excipients and further processed to form a range of pharmaceutical dosage forms and maintain dissolved or molecularly dispersed roflumilast throughout the shelf life of the drug product.

[0026] The present invention also relates to a pharmaceutical composition of roflumilast mixed with a self-emulsifying wax blend of DEGEE and cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate and water, wherein the pH value of the pharmaceutical composition is adjusted to 4.0-6.5.

[0027] The present invention is particularly useful for topical preparations. <1151> Topical roflumilast drug product formulations that may be based on DEGEE-water blends are defined in, including aerosols, foams, sprays, emulsions (also 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).

[0028] Topical administration refers to administration to the skin, hair or nails of a patient who would benefit from the treatment of a pharmaceutical product. Topical can also mean administration to the patient's epithelium for local delivery. This includes, but is not limited to, administration of Roflumilast to the eye, ear, oral mucosa, vaginal mucosa, rectal mucosa or urethra. The most extensive definition of local includes using the patient's epithelium as a route of administration to obtain therapeutic systemic levels of active ingredients. This local definition is commonly referred to as transdermal delivery of therapeutically active ingredients.

[0029] Roflumilast can be prepared by methods known in the art (eg, see the '298 patent and US Patent Application No. 14 / 075,035).

[0030] In topical preparations, DEGEE is generally formulated at 10-30% (w / w), preferably 15-20% (w / w). Likewise, 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. Preferably, in formulations containing roflumilast, the ratio of DEGEE:water is 1:4 to 9:1.

[0031] Typically, the DEGEE-water blend can be used to dissolve up to 2.0% of Roflumilast (in the final product) or preferably up to 0.5% of Roflumilast (in the final product). The final product is preferably in one of the following forms:

[0032] Oil-in-water emulsions: The topical products can be emulsions containing a discontinuous 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 can contain water-soluble or water-swellable polymers that help stabilize the emulsion.

[0033] Water-in-oil emulsions: The composition may be a formulation 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 and 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.

[0034] For oil-in-water and water-in-oil emulsions, the order of addition may be important. Roflumilast can be pre-dissolved in a continuous aqueous phase containing a DEGEE-water blend. Similarly, Roflumilast can be pre-dissolved in the hydrophobic discontinuous phase of the emulsion and then mixed with the DEGEE-water blend and optionally a hydrophilic excipient that does not contain an active ingredient. Roflumilast can be pre-dissolved in the oil phase and the aqueous phase of the emulsion, or pre-dissolved in DEGEE or a DEGEE-water blend after the emulsion is formed. During the cooling of the emulsion, some emulsions undergo phase inversion within a specific temperature range. Therefore, Roflumilast can be added to a water-in-oil emulsion above the phase inversion temperature, and the final drug product is an oil-in-water emulsion at controlled room temperature, or vice versa.

[0035] 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) that has been thickened with 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.

[0036] Thickened hydroalcoholic gels: These systems comprise a DEGEE-water-alcohol blend with dissolved Roflumilast and optionally one or more polar hydrophilic carriers as polar phase (such as hexylene glycol), which has been thickened with a suitable natural, modified natural or synthetic polymer as described below. Alternatively, the thickened hydroalcoholic gel may be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic or anionic system. The alcohol may be ethanol, isopropanol or other pharmaceutically acceptable alcohol.

[0037] Hydrophilic or hydrophobic ointments: These compositions are 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.

[0038] Solvents

[0039] 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 solvent may also change the skin permeability in the topical product or the activity of other excipients contained. 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.

[0040] Moisturizer

[0041] The composition of the present invention may include a humectant to increase the hydration level. For emulsions, the humectant is typically a component of a discontinuous or continuous hydrophobic phase. The humectant may be a hydrophilic substance including a humectant, or may be a hydrophobic substance 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, 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.

[0042] Surfactants and emulsifiers

[0043] The compositions of the present invention optionally include one or more surfactants to emulsify the composition and to help wet the surface of the active ingredient or excipient. As used herein, the term "surfactant" refers to an amphiphile (a molecule with 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 alkyl aryl 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, cocamine oxide, coco betaine, cocodiethanolamide, coco monoethanolamide monoethanolamide), coco-caprylate / caprate, dicetyl phosphate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamidomonoethanolamine sulfosuccinate, sodium docusate, laureth-2, laureth-23, laureth-4, lauric acid diethanolamide, lecithin, methoxy PEG-16, methyl gluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2, oleth-20, PEG6-32 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, P EG-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, Polyoxyl 20 Cetearyl Ether (cetostearyl ether), PEG-40 hydrogenated castor oil, PEG-40 stearate, PEG-6 and PEG-32, PEG-60 glyceryl stearate, PEG-65 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, PPG-26 oleate, PROMULGENTM 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, tallow glycerylglyceride) and emulsifying wax. The preparation preferably contains one or more phosphate surfactants. Examples of phosphate surfactants that can be included in the preparation include, but are not limited to, potassium cetyl phosphate, C9-15 alkyl potassium phosphate, C11-15 alkyl potassium phosphate, C12-13 alkyl potassium phosphate, C12-14 alkyl potassium phosphate, lauryl potassium phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate, ceteth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3 phosphate, oleth-ethyl phosphate Esters, oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4 phosphate, stearyl phosphate, DEA-cetyl phosphate, DEA-oleth-10 phosphate, DEA-oleth-3 phosphate, DEA-C8-C18 perfluoroalkylethyl phosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristyl phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate, trilauryl phosphate, trioleyl phosphate, and tristearyl phosphate.

[0044] Polymers and Thickeners

[0045] For certain applications, it may be desirable to formulate a topical product thickened with a soluble, swellable or insoluble organic polymer thickener (such as natural and synthetic polymers) or an inorganic thickener including, but not limited to, acrylate copolymers, carbomer 1382, carbomer type B copolymers, carbomer type A homopolymers, carbomer type B homopolymers, carbomer type C homopolymers, carboxyvinyl copolymers, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline wax, and methylcellulose.

[0046] Other components

[0047] The composition of the present invention can be formulated with other components such as fillers, carriers and excipients conventionally found in cosmetic and pharmaceutical topical products. Other components include, but are not limited to, defoamers, propellants, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH adjustment solutions, skin penetration enhancers, film formers, dyes, pigments, fragrances and other excipients to improve the stability or aesthetics of the product. In a preferred embodiment, hexylene glycol is added to suppress the change in particle size distribution during the shelf life of the composition. Hexylene glycol can be added by weight / based on weight at 0.1% to 20%, preferably by weight / based on weight at 0.25% to 8%, most preferably by weight / based on weight at 0.5% to 2%.

[0048] In a preferred embodiment, roflumilast is in the form of an aerosol foam, which is particularly suitable for application to the scalp. Any suitable propellant can be used to prepare the aerosol foam. Particularly preferred propellants are isobutane A-31, Aeropin 35, butane 48, dimethyl ether / n-butane-(53 / 47), propane / isobutane / n-butane, propane / isobutane-A70 and propane / isobutane A-46, n-butane (A-17).

[0049] The compositions of the present invention may be formulated with other active agents, depending on the condition to be treated. Other 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 (Propylthouracil), 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarate, corticosteroids (e.g., alclometasone, amcinonide, betamethasone, clobetasol, clocotolone, mometasone, triamcinolone, fluocinolone, fluocinonide, flurandrenolide, diflorasone, desonide, desoximetasone, dexamethasone, halcinonide, halobetasol, hydrocortisone, chlorhexidine ... , methylprednisolone, prednicarbate, prednisone), adrenocorticotropic hormone, vitamin D analogs (e.g., calcipotriene, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, colchicine, adalimumab, ustekinumab, infliximab, bronchodilators (e.g., beta-agonists, anticholinergics, theophylline), and antibiotics (e.g., erythromycin, ciprofloxacin, metronidazole).

[0050] Administration and dosage form

[0051] 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 solutions, oral solutions).

[0052] The composition preferably contains roflumilast, a salt of roflumilast, N-oxide of roflumilast or a salt thereof in an amount of 0.005-2% w / w, more preferably 0.05-1% w / w, most preferably 0.1-0.5% w / w per dosage unit.

[0053] The composition preferably contains 5% to 50% w / w, more preferably 20% to 30% w / w, most preferably 22.5% to 27.5% w / w diethylene glycol monoethyl ether.

[0054] The composition can be administered once or more times a day, preferably the composition is administered 1-2 times a day.

[0055] The composition can be used in veterinary and human medicine to treat and prevent all diseases that can be treated or prevented using 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 by PDE inhibitors; inflammation of the gastrointestinal system or 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.

[0056] The composition may include other active agents suitable for treating the patient's condition. For example, when treating proliferative, inflammatory and allergic skin diseases, the composition may additionally include 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, clocortolone, mometasone, , triamcinolone, fluocinolone acetonide, fluocinolone acetonide, flurandrenolide, diflorasone, desonide, desoximetasone, dexamethasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, prednicarbate, prednisone), adrenocorticotropic hormone, vitamin D analogs (e.g., calcipotriene, calcitriol), acitretin, tazarotene, cyclosporine, resorcinolone, colchicine, adalimumab, ustekinumab, infliximab, and / or antibiotics.

[0057] The following examples are provided to enable those 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 the invention as determined by the inventors. Other advantages and modifications will be apparent to those skilled in the art.

[0058] Example 1

[0059] Table 1

[0060]

[0061]

[0062] Regulations for male and female pigs (Gottingen The animals were 1.0% roflumilast and 2.0% roflumilast. The animals were sedated with Telazol (3-5 mg / kg, IM) for shaving. Care was taken to avoid abrasions of the skin. The cream was applied to the trimmed skin area at 2 grams per kg of pig body weight by gently rubbing with a glass stirring rod or an appropriate utensil (e.g., a stainless steel spatula). The cream was applied evenly to form a thin, uniform film starting from the scapular region and moving to the tail of the test site. The width of the test site area was separated along both sides of the spine. Equal numbers of male and female pigs were administered 1.0%, 0.5%, 0.3%, or 0.15% roflumilast cream. Blood was collected from the anterior vena cava through the thoracic inlet or other suitable vein before dosing (time = 0), 1, 2, 4, 8, and 24 hours after dosing. The lag time was calculated by extrapolating the average 1-hour and 2-hour plasma concentrations to the time point when the roflumilast concentration in the plasma was zero. For individual animals with a 1-hour plasma analysis below the quantitative level (0.2 ng / mL), a value of 0.1 was used if the 2-hour PK time point was above 0.2 ng / mL. If the 2-hour PK time point was below the quantitative level, a value of 0 ng / mL was used for each animal to calculate the mean. For each roflumilast cream at pH = 5.5, the lag time was less than 1 hour, regardless of the concentration of roflumilast.

[0063] Table 2

[0064]

[0065] Example 2

[0066] Table 3

[0067]

[0068] Table 4

[0069]

[0070] An in vitro skin permeation test (IVPT) was used to determine how quickly eight different cream formulations penetrated excised human skin. Human cadaver skin was obtained from two donors (Caucasian male age = 30, abdominal skin, excised to an average thickness of 510 μm; Caucasian male age = 55, abdominal skin, excised to an average thickness of 360 μm). Excised skin was received frozen from a US tissue bank and stored at -20°C until use. The skin was mounted to a diffusion area of ​​0.503 cm 2 (8mm in diameter) Franz vertical diffusion cell, and fill the receptor cavity with 3.0ml of 4% BSA in water containing 0.01% gentamicin sulfate (constant temperature at 32°C). Using an external piston pipette (positive displacement pipette), 5 microliters of cream (10 mg per square centimeter of skin) were administered on each Franz vertical diffusion cell. The receptor solution was analyzed using a validated LC-MS / MS (Kinetex C18, 5μm, 2.1x 50mm column, Shimadzu LC20ADXR pump and AB SciexAPI 4000Turbo Spray detector). The cumulative amount of roflumilast measured in the receptor solution is the average of four repeated IVPT measurements.

[0071] like Figure 3 As shown in , five creams containing Crodafos CES as an emulsifier had measurable levels of roflumilast in the receptor solution one hour after administration. These creams had essentially the same extrapolated lag time of 50-60 minutes, with a lag time of slightly less than 1 hour when the pH was adjusted to 5.0 to 6.5. Removal of hexylene glycol from the Crodafos CES cream formulation produced a product with the shortest lag time (i.e., the highest concentration of roflumilast at 1 hour (0.4 ng / mL)). It was concluded that hexylene glycol is not an excipient that causes roflumilast to rapidly cross the human stratum corneum (i.e., IVPT lag time of less than 1 hour).

[0072] DES, DIA, and PEG creams did not transport significant amounts of roflumilast across human skin until three hours after a dose of the cream was applied. Two of the three long lag-time cream formulations contained methylparaben, and one contained both methylparaben and propylparaben. In conclusion, the low levels of methylparaben and propylparaben required to preserve the cream did not shorten the lag time of roflumilast across the skin.

[0073] DES cream contains light mineral oil, while DIA cream contains paraffin. Mineral oil is a low molecular weight fraction of petrolatum, while paraffin is a high molecular weight fraction of petrolatum. This suggests that the surprisingly short lag time of Crodafos CES cream is due to the cream containing Crodafos CES, DEGEE or a combination thereof.

[0074] Example 3

[0075] Table 5

[0076]

[0077]

[0078] Regulations for male and female pigs (Gottingen The animals were 400-600 swine (400-600 swine) and 400-700 swine (400-700 swine) with a weight of 8-12 kg upon arrival. The hair was clipped from the back of each animal one day before administration of a topical cream containing 0.15% roflumilast. The animals were sedated with Telazol (3-5 mg / kg, IM) for the shaving procedure. Care was taken to avoid abrasions of the skin. Gently rub with a glass stirring rod or an appropriate utensil (e.g., a stainless steel spatula) and distribute the cream to the trimmed skin area in an amount of two (2) grams per kilogram of pig body weight. The cream was applied evenly to form a thin, uniform film starting from the scapular area and moving to the tail of the test site. The width of the test site area was divided along both sides of the spine. Six pigs (3 males and 3 females) were administered a 0.15% roflumilast topical semisolid product, and twelve pigs (6 males and 6 females) were administered a 0.15% roflumilast cream. Before administration (time = 0), 1, 2, 4, 8 and 24 hours after administration, blood was collected from the anterior vena cava through the thoracic inlet or other suitable veins. The lag time was calculated by extrapolating the average 1 hour and 2 hour plasma concentration to the time point when the roflumilast concentration in the plasma was zero. For a single animal with a 1 hour plasma analysis below the quantitative level (0.2 ng / mL), if the 2 hour PK time point was higher than 0.2 ng / mL, a value of 0.1 was used. If the 2 hour PK time point was lower than the quantitative level, the value of 0 ng / mL was used to calculate the mean value for each animal. For all local semi-solid preparations of pH = 6.5 or lower, the lag time was less than 1 hour, and for the semi-solid with a pH value of 8.2, the lag time was significantly greater than 1 hour.

[0079] Table 6

[0080]

[0081] Example 4

[0082] Accurately weigh a target amount of 480 grams of Sterile Water for Irrigation-USP into a 1000 ml glass beaker, then add 20 grams of Sodium Hydroxide Granular-NF and mix with a stir bar until completely dissolved. Set this solution aside and label it 1N Sodium Hydroxide.

[0083] The target weight of 1000 g of white petrolatum-USP, 500 g of isopropyl palmitate-NF and 1000 g of phosphate self-emulsifying wax (CRODAFOS TM CES) was weighed into a 4 L glass beaker and heated to 75°C to 80°C on a hot plate with mixing by a propeller mixer. This mixture was labeled the oil phase and was maintained at 75°C to 80°C.

[0084] Add a target weight of 4225 grams of Sterile Water for Rinsing - USP and a target weight of 300 grams of 1 N Sodium Hydroxide to the main manufacturing vessel (20 L stainless steel vessel) and heat on a hot plate to 75° C. to 80° C. Record this as the water phase and maintain at 75° C. to 80° C.

[0085] A target weight of 2400 g of Transcutol P-NF, 200 g of hexylene glycol-NF, 20.0 g of methylparaben-NF and 5.0 g of propylparaben-NF was accurately weighed into a 7 L stainless steel beaker and mixed with a propeller until a clear homogeneous solution was obtained. Sufficient potency-corrected roflumilast (15.2120 g) was added to the solution to obtain a 0.15% roflumilast cream, which was labeled as the API phase.

[0086] Slowly add the oil phase maintained at 75°C to 80°C to the water phase maintained at 75°C to 80°C in the main manufacturing vessel and mix with a homogenizer until a smooth and uniform cream is obtained. Cool the cream to 45°C to 50°C using propeller mixing. Slowly add the API phase to the cream in the main manufacturing vessel and mix with a homogenizer. Measure the pH of the finished cream and adjust it to a pH range of 5.1 to 5.9 using 1N Sodium Hydroxide or 10% (w / w) dilute HCl-NF. After the batch product is released, the cream is packed into aluminum 3 / 4" x 3 3 / 4" #16 sealed white tube which is crimped to provide the primary container closure system.

[0087] Thirteen human subjects with psoriasis (plaque coverage of no more than 5% of the patient's body surface area) were treated with the 0.15% roflumilast cream formulation of Example 3 for their skin lesions. One hour after the first application of the topical cream, blood samples were collected, plasma was separated, and the concentration of roflumilast was determined using a validated bioanalytical method. The mean plasma concentration of roflumilast in these 13 subjects was 0.398 ng roflumilast / mL plasma one hour after the first administration of the topical cream. The lag time for psoriasis patients who were administered 0.15% roflumilast cream was less than 1 hour.

[0088] Example 5

[0089] The same manufacturing process as in Example 3 was performed except that a sufficient amount of potency-corrected roflumilast (50.69 g) was added to the API phase solution to obtain a 0.5% roflumilast cream.

[0090] Fifteen human subjects with psoriasis (plaque coverage of no more than 5% of the patient's body surface area) were treated with the 0.5% roflumilast cream formulation of Example 2 for their skin lesions. One hour after the first application of the topical cream, blood samples were collected, plasma was separated, and the concentration of roflumilast was determined using a validated bioanalytical method. The mean plasma concentration of roflumilast in these 15 subjects was 0.595 ng roflumilast / mL plasma one hour after the first administration of the topical cream. The lag time for psoriasis patients who were administered 0.5% roflumilast cream was less than 1 hour.

Claims

1. Use of a composition comprising 0.005-2% w / w of roflumilast and an emulsifier blend in the preparation of a medicament for treating inflammatory skin diseases, the medicament being for topical administration and having a roflumilast skin penetration lag time in a patient of less than 60 minutes, wherein the emulsifier blend comprises cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate, and wherein the composition has a pH of 4.0-6.

5.

2. The use according to claim 1, wherein the composition further comprises diethylene glycol monoethyl ether.

3. The use according to claim 1, wherein the roflumilast skin penetration lag time is less than 60 minutes.

4. The use according to claim 3, wherein the roflumilast skin penetration lag time is less than 45 minutes.

5. The use according to claim 1, wherein the patient suffers from atopic dermatitis or psoriasis.

6. Use of a composition comprising 0.005-2% w / w of roflumilast, a phosphate surfactant and diethylene glycol monoethyl ether in the preparation of a medicament for treating inflammatory skin diseases, the medicament being for topical administration and having a roflumilast skin penetration lag time in a patient of less than 60 minutes, wherein the pH of the composition is 4.0-6.

5.

7. The use according to claim 6, wherein the skin penetration lag time of the composition is less than 60 minutes.

8. The use according to claim 6, wherein the inflammatory skin disease is atopic dermatitis or psoriasis.

9. The use according to claim 1, wherein the amount of roflumilast is 0.05-1% w / w.

10. The use according to claim 9, wherein the amount of roflumilast is 0.1-0.5% w / w.

11. The use according to claim 10, wherein the amount of roflumilast is 0.3% w / w.

12. The use according to claim 6, wherein the amount of roflumilast is 0.05-1% w / w.

13. The use according to claim 1, wherein the roflumilast composition is selected from the group consisting of an oil-in-water emulsion, a thickened aqueous gel, a thickened hydroalcoholic gel, a hydrophilic gel, and a hydrophilic or hydrophobic ointment.

14. The use according to claim 1, wherein the roflumilast composition further comprises at least one other component selected from the group consisting of a solvent, a moisturizer, a preservative, a pH adjusting solution, and a skin penetration enhancer.

15. The use according to claim 12, wherein the amount of roflumilast is 0.1-0.5% w / w.

16. The use according to claim 15, wherein the amount of roflumilast is 0.3% w / w.

17. A pharmaceutical composition comprising 0.005-2% w / w of roflumilast, a) an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, b) diethylene glycol monoethyl ether, and c) isopropyl palmitate, wherein the composition does not comprise hexylene glycol, and wherein the pH of the composition is 4.0-6.

5.

18. The composition of claim 17, wherein the composition has a lag time of less than 60 minutes.

19. The composition of claim 17, wherein the amount of roflumilast is 0.05-1% w / w.

20. The use according to claim 1, wherein the pH of the composition is 5.0-6.

5.

21. The use according to claim 1, wherein the amount of the emulsifier blend is 10% w / w.

22. The composition of claim 19, wherein the amount of roflumilast is 0.3% w / w.

23. The use according to claim 6, wherein the amount of diethylene glycol monoethyl ether is 10-30% w / w.

24. The use according to claim 6, wherein the amount of diethylene glycol monoethyl ether is 25% w / w.

25. The use according to claim 2, wherein the amount of diethylene glycol monoethyl ether is 10-30% w / w.

26. Use according to claim 25, wherein the amount of diethylene glycol monoethyl ether is 25% w / w.

27. The use according to claim 1, wherein the composition is a foam or a cream.

28. The use according to claim 27, wherein the composition is a foam.

29. The use according to claim 27, wherein the composition is a cream.

30. The use according to claim 6, wherein the composition is a foam or a cream.

31. The use according to claim 30, wherein the composition is a foam.

32. The use according to claim 30, wherein the composition is a cream.

33. The composition of claim 17, wherein the pharmaceutical composition is a foam or a cream.

34. The composition of claim 33, wherein the pharmaceutical composition is a foam.

35. The composition of claim 33, wherein the pharmaceutical composition is a cream.

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