Methods of reducing side effects of administration of phosphodiesterase-4 inhibitors

Abstract

The present invention relates to methods of reducing side effects of administration of a phosphodiesterase-4 inhibitor. In particular, the present invention relates to a method of altering the PK spectrum of a pharmaceutical formulation containing a PDE-4 inhibitor, such as roflumilast, to reduce the spike of Cmax. The spike of Cmax is reduced by topical administration after combination of a PDE-4 inhibitor with one or more phosphate ester surfactants. Reducing the spiking of Cmax will reduce gastrointestinal side effects and lead to better patient compliance.

Description

[0001] This application is a divisional application of PCT application PCT / US2020 / 029008, filed on April 20, 2020, with the invention name “Method for Reducing Side Effects of Administering Phosphodiesterase-4 Inhibitors”. The application number of the PCT application after entering the Chinese national phase is 202080075942.X. Technical Field

[0002] The present invention relates to the field of topical medicines for treating medical conditions. In particular, the present invention relates to topical preparations containing an active pharmaceutical ingredient which is a phosphodiesterase-4 inhibitor. The preparations are pharmaceutically effective and can reduce gastrointestinal side effects. Background Art

[0003] Drugs that inhibit phosphodiesterase-4 (PDE-4) have been found to be useful for the medical treatment of many medical conditions, most notably psoriatic arthritis, psoriasis, atopic dermatitis, asthma and chronic obstructive pulmonary disease (COPD). Examples of such drugs include apremilast, cilomilast, crisaborole, ibudilast, picamilast, roflumilast and rolipram. Although these drugs are clinically useful, due to the side effects associated with their use, including diarrhea, weight loss, nausea, headache, back pain, insomnia, dizziness, flu-like symptoms and a high incidence of decreased appetite, their use is sometimes limited. These side effects, particularly gastrointestinal side effects, can have a significant impact on patient compliance.

[0004] Roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyridin-yl]-benzamide) and its active metabolite, roflumilast N-oxide (3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyridin-4-yl 1-oxide) benzamide) described herein are representative members of a class of drugs that inhibit PDE-4. Roflumilast is known to be suitable as a bronchial therapeutic agent and for treating inflammatory conditions. Compositions containing roflumilast are used in human and veterinary medicine and are suggested for the treatment and prevention of diseases including, but not limited to: inflammatory and allergen-induced airway conditions (such as bronchitis, asthma, COPD); skin diseases (such as proliferative, inflammatory and allergen-induced skin diseases), and general inflammation of the gastrointestinal region (Crohn's disease and ulcerative colitis). Currently, roflumilast is systemically administered to treat inflammatory conditions involving the lungs, such as asthma and chronic obstructive pulmonary disease (COPD).

[0005] 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, the reference incorporated herein by reference is incorporated in its entirety for all purposes). (AstraZeneca Pharmaceuticals LP, Wilmington, DE) and in Europe under the trade name (Takeda GmbH, Konstanz, Germany) was approved. and Both are 500mcg tablets taken orally once daily for the treatment of chronic obstructive pulmonary disease (COPD).

[0006] Due to the high incidence of gastrointestinal side effects, including severe nausea and diarrhea, The prescribing information for levofloxacin instructs to take half the therapeutically effective dose, 250 mcg, once daily for 4 weeks prior to starting the therapeutically effective dose of 500 mcg once daily to reduce the rate of treatment discontinuation. The prescribing information for levofloxacin does not instruct patients to take a reduced nontherapeutically effective dose before taking a therapeutic dose. The prescribing information for levofloxacin does report high rates of diarrhea, nausea, and abdominal pain associated with the drug.

[0007] When roflumilast is administered orally, the drug is rapidly absorbed, resulting in sharp spikes in plasma concentrations. According to documents submitted to the FDA, when roflumilast tablets were initially administered, the Cmax (peak plasma concentration) for the 500mcg tablet was 7.34mcg / l, peaking at Tmax (time to reach Cmax after administration) 1 hour after administration, and the Cmax for the 250mcg tablet was 3.99mcg / l, peaking at Tmax 1 hour after administration. The spike in Cmax followed a clear dose-response relationship. The occurrence of gastrointestinal side effects also showed a similar dose-response relationship, indicating that these side effects were related to the spike in Cmax.

[0008] When multiple oral doses of roflumilast are administered, exposure follows a "peak to trough" pattern. This results in sporadic changes in drug blood levels and persistent gastrointestinal side effects due to re-emergence of high, spiked Cmax levels after each administration of the drug.

[0009] Bolle, U.S. Patent Application Publication No. 2006 / 0084684 discloses topical formulations of roflumilast, salts of roflumilast, N-oxides of roflumilast, and salts of N-oxides. Bolle discloses that these formulations can be applied to skin lesions for topical treatment of skin diseases, or topically applied for systemic treatment of skin diseases and other conditions (such as COPD). Bolle discloses that the systemic effects of topical roflumilast formulations are comparable to those of oral dosage forms.

[0010] Bolle further discloses in paragraph 0080 that “comparison with oral administration indicated that, regardless of the composition of the topical formulation, similar Cmax and AUC were achieved and similar excretion in the urine was achieved.”

[0011] Although Bolle did not discuss the incidence of side effects following topical administration of roflumilast formulations, because the Cmax of topical formulations was similar to the Cmax of orally administered formulations regardless of the components of the topical formulations, and because side effects are related to Cmax, it can be expected that the administration of any topical formulation, regardless of its components, would result in a similar incidence of side effects as the orally administered formulation.

[0012] Although oral tablets of Roflumilast have been commercialized, topical and parenteral administration require different formulations due to the low water solubility of the compound, reported in WO95 / 01338 (corresponding to the '298 patent, incorporated herein by reference) as only 0.53 mg / l at 21°C. This low water solubility is problematic for developing parenteral formulations and topical emulsions, suspensions, gels or aqueous solutions. In US 9,205,044 (incorporated herein by reference) the low water solubility of Roflumilast was overcome by using alkoxylated fats, particularly polyoxyethylene 12-hydroxystearic acid, as a cosolvent for parenteral administration. In US 9,884,050 (incorporated herein by reference) the low water solubility of Roflumilast was overcome by using hexylene glycol. In EP1511516B1 (corresponding to published U.S. application Ser. No. 14 / 075,035), the low water solubility of roflumilast was overcome in a topical emulsion (cream) formulation by formulating with polyethylene glycol 400 (PEG 400) at a concentration exceeding 62% (w / w) while keeping the water weight percentage below 10%.

[0013] Topical application of potent pharmacological agents such as roflumilast has been found to provide superior delivery and greater convenience to patients. The molecular structure of the compound ultimately determines the ability of the drug to penetrate the epithelium of the tissue to which the product is applied. For topical application to the skin, the choice of formulation components determines the maximum skin permeability that the formulation 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 use on the skin.

[0014] It would be advantageous to develop and provide a pharmaceutical formulation containing a PDE-4 inhibitor, such as roflumilast, which, when systemically administered at a therapeutically effective dose, does not result in a sharp peak in Cmax while still providing a high AUC, and which is therefore pharmaceutically effective and associated with a reduced incidence of gastrointestinal side effects. Summary of the invention

[0015] According to the present invention, it has been found that adding one or more phosphate surfactants to a topical formulation containing a PDE-4 inhibitor reduces the peak of Cmax while still producing a high AUC. The reduction in the peak of Cmax reduces gastrointestinal side effects, which will lead to better patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is a line graph comparing the pharmacokinetic (PK) profiles of two formulations of the present invention, Formulation 1 and Formulation 2, and the PK profile of a prior art formulation (Formulation 3).

[0017] Figure 2 is a graph comparing the slow rise to Cmax with Formulation 4 (dicetyl phosphate / cetoeth-10 phosphate) with the significantly greater peak roflumilast Cmax (compared to trough T=0 plasma concentration) after dosing with Comparative Formulation 5 (potassium cetyl phosphate) and Comparative Formulation 6 (cetostearyl alcohol and glyceryl stearate / PEG-100 stearate).

[0018] Figure 3 is a line graph showing the PK profiles of roflumilast 0.15% topical cream on Day 1 and Day 28 following once daily administration.

[0019] Figure 4 is a line graph showing the PK profiles of roflumilast 0.3% topical cream on Day 1 and Day 14 after once daily administration.

[0020] Figure 5 is a line graph showing the PK profiles of roflumilast 0.5% topical cream on Day 1 and Day 28 after once daily administration.

[0021] Figure 6is a line graph showing the PK profiles of roflumilast 1.0% topical cream on Day 1 and Day 28 following once daily administration.

[0022] 7A, 7B, and 7C show the change from baseline in target plaque severity scores and / or target plaque areas for 0.15% roflumilast topical cream and 0.5% roflumilast topical cream.

[0023] Fig. 8A and 8B Plasma concentrations of roflumilast and roflumilast N-oxide on Day 1 and Day 28 are shown for 0.15% roflumilast topical cream and 0.5% roflumilast topical cream (pharmacokinetic population).

[0024] Fig. 9 The PDE4 inhibitor crisaborole was shown to be effective in patients taking once daily Line graph of the pharmacokinetic profiles at day 1 single dose and day 8 steady state following topical ointment.

[0025] Fig.10 is a line graph showing the single-dose PK profile on day 1 following once-daily administration of Crodafos-CES cream containing either 0.3% crisaborole or 0.3% roflumilast. DETAILED DESCRIPTION

[0026] The term "PDE-4 inhibitor" refers to one or more members of a class of drugs that, when administered to a human, inhibit phosphodiesterase-4. Examples of such drugs include apremilast, cilomilast, crisaborole, ibudilast, picamilast, roflumilast, and rolipram.

[0027] The term "Roflumilast" used in this application, unless otherwise specified or clearly indicated in the context is Roflumilast itself, refers to Roflumilast, its salts, Roflumilast N-oxides and salts thereof. The terms "N-oxide of Roflumilast" and "Salts of Roflumilast or N-oxide of Roflumilast" specifically refer to N-oxides or Roflumilast or salts of its N-oxide. Roflumilast described herein is both a representative member of the PDE-4 inhibitor class and Roflumilast itself, which, depending on the context, includes Roflumilast itself, its salts, Roflumilast N-oxides and salts of the N-oxides. Roflumilast preparations can be prepared by methods known in the art (e.g., see the '298 patent and U.S. Application No. 14 / 075,035).

[0028] Roflumilast is a compound of formula (I):

[0029]

[0030] wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyridin-4-yl.

[0031] The chemical name of this compound is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: Roflumilast).

[0032] The term "salt" when referring to Roflumilast or the N-oxide of Roflumilast refers to the salts described in paragraphs

[0012] and

[0013] of US Patent Application Publication No. US2006 / 0084684, the disclosures of which are incorporated herein by reference.

[0033] It has been unexpectedly discovered, in direct contrast to the doctrine of the prior art, that pharmaceutical formulations, such as topically applied pharmaceutical formulations containing a PDE-4 inhibitor, such as roflumilast, can provide an altered PK (pharmacokinetic) profile, a reduced Cmax or a reduced absorption rate to reach Cmax, when the formulation contains one or more phosphate ester surfactants, compared to a pharmaceutical formulation containing a PDE-4 inhibitor without a phosphate ester surfactant. In particular, it has been unexpectedly discovered that pharmaceutical formulations containing roflumilast and one or more phosphate ester surfactants, when topically administered to a subject, provide systemic effective levels of a PDE-4 inhibitor comparable to, or even higher than, the levels achieved with oral administration, through slow absorption and the absence of a Cmax spike in the entry of the PDE-4 inhibitor into the blood.

[0034] In terms of pharmacokinetics, a formulation containing a PDE-4 inhibitor drug, such as roflumilast and a phosphate surfactant, when administered to an individual, such as by topical application to the individual's skin, can provide a sufficiently high area under the curve (AUC) to achieve a systemic effective level of the PDE-4 inhibitor drug without rapidly producing a peak plasma concentration (Cmax) associated with gastrointestinal side effects. That is, when the formulation of the present application is administered, the absorption rate of the drug to reach Cmax is reduced compared to the administration of the formulation of the prior art.

[0035] As used herein, the term "absorption rate to Cmax" refers to the slope of the PK curve between administration of a formulation containing a drug and Cmax, or refers to the slope of the PK curve between the trough and the adjacent peak after continuous multiple-dose administration of a formulation.

[0036] Therefore, unlike the teachings of the prior art, the preparations of the present application unexpectedly have significantly different PK profiles compared to the prior art preparations containing PDE-4 inhibitors. The preparations of the present application provide sufficiently high AUC to reach the systemic effective level of the PDE-4 inhibitor without producing a spike in Cmax. The gradual rise in Cmax obtained after topical application of the preparations of the present invention is significantly different from the preparations of the prior art, but the AUC is similar. In addition, after applying multiple doses of the preparations, the PK profile does not have an initial Cmax spike and a peak to trough pattern, which is obtained after multiple daily administrations using the prior art preparations containing the drug.

[0037] This discovery provides some unexpected advantages. First, it provides a method for treating medical conditions that respond to the administration of PDE-4 inhibitors, which can minimize the incidence of adverse side effects, particularly GI side effects. This in turn leads to greater patient compliance and reduces the incidence of discontinuation of treatment due to the development of such side effects.

[0038] In addition, due to the very slow rise to Cmax and the avoidance of Cmax spikes, the formulations of the present invention can produce higher systemic exposure levels (AUC) than prior art formulations, and there are no side effects associated with Cmax spikes, such as side effects of the GI system. This previously unobtainable exposure level will provide greater efficacy for the treatment of diseases.

[0039] In addition, it was unexpectedly found that after reaching Cmax after administration, the blood level of the drug had a very gentle and long plateau period. In addition, the PK profile obtained by the preparation of the present application after multiple administrations was extremely and unexpectedly gentle and long-lasting, and after 28 days of administration, the fluctuation from peak to trough was extremely small. When the preparation further contained diethylene glycol monoethyl ether, the gentleness of this PK profile was particularly obvious.

[0040] Because absorption of the amount of PDE-4 inhibitor required to provide a therapeutic effect from the formulation is not dependent on an absorption spike to provide a high Cmax, and because absorption of the PDE-4 inhibitor is steady and has a flat PK profile, an individual user of the formulation can occasionally miss doses and still maintain therapeutic efficacy.

[0041] An important advantage of the formulation of the present invention is that, due to the very slow rise to Cmax and the avoidance of Cmax spikes, the formulation of the present invention allows for higher systemic exposure levels (AUC) than prior art formulations, and without the side effects associated with Cmax spikes, such as side effects of the GI system. Such previously unachievable exposure levels will provide greater efficacy for the treatment of diseases.

[0042] In a first embodiment, the invention is a pharmaceutical formulation for administering a PDE-4 inhibitor drug to an individual in need thereof.

[0043] According to this embodiment, the pharmaceutical preparation of the present invention contains one or more PDE-4 inhibitor drugs. Such PDE-4 inhibitor drugs may include Apremilast, Cilomilast, Clisborole, Ibudilast, Pilamilast, Roflumilast and / or Rolipram. In a preferred embodiment, the preparation contains Roflumilast. The concentration of the PDE-4 inhibitor drug refers to a concentration sufficient to improve the medical condition of the response to the administration of the PDE-4 inhibitor drug, such as psoriatic arthritis, psoriasis, atopic dermatitis, asthma and chronic obstructive pulmonary disease (COPD).

[0044] The preparation further contains one or more phosphate surfactants. Examples of phosphate surfactants that may be included in the present application preparation include, but are not limited to, potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl 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 alcohol phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate , oleth-3 phosphate, oleyl alcohol phosphate, oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteareth-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 perfluoroalkylethanol phosphate, dicetyl phosphate, dilaureth-10 phosphate, myristyl alcohol diester phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate, trilauryl phosphate, trioleyl phosphate and tristearyl phosphate.

[0045] In addition to one or more phosphate surfactants, the formulation may optionally contain diethylene glycol monoethyl ether. Diethylene glycol monoethyl ether is also known as 2-(2-ethoxyethoxy)ethanol, or DEGEE, and is sold under a variety of trade names, including (Gattefosse Corporation, Paramus, NJ), CARBITOLTM (The Dow Chemical Company, Midland, MI), (Shell Oil Company, Houston, TX) and POLY-SOLV DM (Monument Chemical, Houston, TX).

[0046] DEGEE is usually added to topical products as a cosolvent to increase the solubility of the drug in the formulation. Adding DEGEE to topical formulations has also been shown to enhance skin permeability, i.e., increase the Cmax of topically applied drug actives. See Javadzadeh et al, Chapter 12, pages 195-205, Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Modification of the Stratum Corneum, (N. Dragicevic, HIMaibach, eds) Springer-Verlag Berlin Heidelberg 2016.

[0047] The concentration of a PDE-4 inhibitor, such as Roflumilast, in a formulation is a concentration sufficient to obtain the desired systemic pharmacological effect when the formulation is applied to the skin of an individual. This concentration necessarily varies based on the specific PDE-4 inhibitor contained in the formulation and the disease or condition to be treated. For Roflumilast, the concentration in the formulation is generally in the range of 0.001 to 25% w / w, preferably in the range of 0.01 to 5%, more preferably in the range of 0.05 to 1%, and most preferably in the range of 0.1 to 0.5%. In a specific preferred embodiment, the concentration of Roflumilast in the formulation is in the range of 0.05 to 0.5%, such as 0.05%, 0.15%, 0.3% and 0.5% w / w.

[0048] The concentration of the phosphate surfactant in the formulation is sufficient to produce a stable emulsion with uniform spherical size. If necessary, a lower concentration of the phosphate surfactant can be combined with other emulsifiers to produce a stable emulsion with uniform droplet size. The phosphate surfactant can also increase the solubility of Roflumilast in the cream. The concentration of the phosphate surfactant can generally be any concentration from 1.0% to 25% w / w. For different forms of application, the preferred concentration can be different. In a preferred embodiment, when the formulation is a cream or ointment, the concentration of the phosphate surfactant is 2.5% to 20%, a more preferred concentration range is 5% to 15%, and a most preferred concentration is about 10% w / w. When the formulation is in the form of a foam, the concentration is preferably 1.0%-10%, more preferably 1.0%-10%, and most preferably 2%.

[0049] If diethylene glycol monoethyl ether is present in the formulation, its concentration is sufficient to dissolve the active pharmaceutical ingredient. Diethylene glycol monoethyl ether can also enhance the skin permeability of roflumilast. Generally, the concentration of diethylene glycol monoethyl ether is 5% to 50% w / w, the preferred concentration range is 10% to 40% w / w, the more preferred range is 15% to 30% w / w, and the particularly preferred concentration is about 15-25% w / w. Similarly, in topical products, water is formulated to be about 20-90% (w / w). 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. Typically, DEGEE-water blends can be used to dissolve up to 2.0% roflumilast (in the final product) or preferably up to 0.5% roflumilast (in the final product).

[0050] The preparation for topical application to the skin is preferably a semisolid dosage form, which is superficially applicable to the skin and is easy to apply to the skin. Examples of such semisolid dosage forms include emulsions, ointments, creams, gels and pastes. Alternatively, the preparation can be in a form other than a semisolid dosage form, such as a liquid, which can be applied as a spray or foam. Preferably, the preparation for topical application is one of the following forms:

[0051] Oil-in-water emulsions: Topical products can be emulsions comprising 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 include water-soluble or water-swellable polymers that help stabilize the emulsion.

[0052] Water-in-oil emulsions: The composition may be a formulation in which Roflumilast is incorporated into an emulsion, which includes a continuous hydrophobic phase and an aqueous phase, the aqueous phase including a DEGEE-water blend and optionally one or more polar hydrophilic carriers and salts or other components. These emulsions may include an oil-soluble or oil-swellable polymer and one or more emulsifiers that help stabilize the emulsion.

[0053] 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 a DEGEE-water blend and an optional 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 Roflumilast pre-dissolved in DEGEE or a DEGEE-water blend can be added after the emulsion is formed. Some emulsions undergo phase inversion within a specific temperature range during the cooling of the emulsion. 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.

[0054] Thickened aqueous gels: These systems include 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.

[0055] Thickened hydroalcoholic gels: These systems include DEGEE-water-alcohol blends with dissolved Roflumilast and optionally one or more polar hydrophilic carriers (such as hexylene glycol) as the polar phase, thickened by suitable natural, modified natural or synthetic polymers as described below. In addition, thickened hydroalcoholic gels can be thickened using suitable polyethoxylated alkyl chain surfactants or other nonionic, cationic or anionic systems. The alcohol can be ethanol, isopropanol or other pharmaceutically acceptable alcohols.

[0056] Hydrophilic or hydrophobic ointment: The composition is formulated with a hydrophobic base (such as petrolatum, thickened or gelled water-insoluble oils, etc.) and optionally a small amount of DEGEE-water blend with dissolved roflumilast. Hydrophilic ointments generally contain one or more surfactants or wetting agents.

[0057] In addition to the PDE-4 inhibitor (such as roflumilast) and the phosphate surfactant (with or without the optional presence of diethylene glycol monoethyl ether), the formulation may contain other excipients commonly found in such dosage forms. Such excipients will vary depending on the type and desired properties of the dosage form.

[0058] Solvents

[0059] The composition of the present invention may include one or more solvents or cosolvents to obtain the solubility of the active ingredient in the product at the desired level. The solvent may also change the skin permeability or activity of other excipients contained in the topical product. The solvent includes but is 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-methyl pyrrolidone, propylene glycol and SD alcohol.

[0060] Moisturizer

[0061] The composition of the present invention may include a humectant to increase the hydration level. For emulsions, the humectant is typically a component of the discontinuous or continuous hydrophobic phase. The humectant may be a hydrophilic substance including a humectant, or it may be a hydrophobic substance including an emollient. Suitable humectants include, but are not limited to: 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerol, polyethylene glycol 200-8000, butyl stearate, cetearyl alcohol, cetyl alcohol, cetyl alcohol ester wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, behenyl alcohol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, monostearate Glycerides, Glyceryl Oleate, Glyceryl Palmitate, Glycol Distearate, Glycol Stearate, Isostearic Acid, Isostearyl Alcohol, Lanolin, Mineral Oil, Light Mineral Oil, Lanolin, Limonene, Medium Chain Triglycerides, Menthol, Myristyl Alcohol, Octyldodecanol, Oleic Acid, Oleyl Alcohol, Oleyl Oleate, Olive Oil, Paraffin, Peanut Oil, Petrolatum, Plastibase-50W, Sorbitol, Stearic Acid, Stearyl Alcohol, and Urea.

[0062] Surfactants and emulsifiers

[0063] The compositions of the present invention may 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 amphiphilic molecule (a molecule having 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, cholestereth-24, cocamide ether sulfate, cocamide oxide, coco Betaine, Cocoyl Diethanolamine, Coconut Monoethanolamine, Coco-Caprylate / Caprate, Cetyl Phosphate, Disodium Cocoamphodiacetate, Disodium Laureth Sulfosuccinate, Disodium Laureth Sulfosuccinate, Disodium Laureth Sulfosuccinate, Disodium Oleamide Monoethanolamine Sulfosuccinate, Sodium Docusate, Laureth-2, Laureth-23, Laureth-4, Laureth 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 / 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 Laureth Acid, PEG-8 stearate, polyethylene glycol 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 alcohol ether, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 40 stearate, polyoxyethylene 6 and polyoxyethylene 32, polyoxyethylene stearic acid glyceryl, polyoxyethylene stearate, polyoxyethylene stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, 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 glyceryl and emulsifying wax.

[0064] Suitable phosphate surfactants include, but are not limited to, potassium cetearyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl 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, octyldecanol phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-6 phosphate, oleth-7 phosphate, octyldodecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-8 phosphate, octyldodecyl phosphate, oleth-20 ...20 phosphate, oleth-8 phosphate, octyldodecyl phosphate, oleth-20 phosphate, oleth-20 phosphate, oleth-20 phosphate, oleth-20 phosphate, oleth-20 phosphate, octyldodecyl phosphate, oleth Ceteareth-3 Phosphate, Oleyl Alcohol Phosphate, Oleyl Phosphate, PEG-26-PPG-30 Phosphate, PPG-5 Ceteareth-10 Phosphate, PPG-5 Ceteareth-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 Perfluoroalkyl Alcohol Phosphate, Dicetyl Phosphate, Dilaureth-10 Phosphate, Myristyl Diphosphate, Dioleyl Phosphate, Tricetyl Phosphate, Triceteareth-4 Phosphate, Trilaureth-4 Phosphate, Trilauryl Phosphate, Trioleyl Phosphate, and Tristearyl Phosphate.

[0065] Polymers and Thickeners

[0066] In some applications, it may be desirable to formulate a topical product that is thickened with a soluble, swellable or insoluble organic polymeric thickener, such as natural and synthetic polymers or inorganic thickeners, including but not limited to acrylic copolymers, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, polyacrylic acid, carboxymethylcellulose, carbopol, carrageenan, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline wax and methylcellulose.

[0067] The formulation may contain one or more thickeners to provide viscosity so that the formulation can be provided in a semi-solid form, such as a lotion, gel, cream or ointment. Examples of suitable thickeners include, but are not limited to, soluble, swellable or insoluble organic polymeric thickeners, such as natural and synthetic polymers or inorganic thickeners, including, but not limited to, acrylic copolymers, carbomer 1382, copolymer B type, carbomer homopolymer A type, homopolymer B type, carbomer homopolymer C type, carbomer, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, gum arabic, alginic acid, bentonite, carbomer (also known as polyacrylic acid, for example, (Lubrizol, Wickliffe, Ohio) is sold as a trade name), carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate, methyl cellulose, poloxamer, polyvinyl alcohol, sodium alginate, tragacanth gum and xanthan gum. The thickener may be present in the oil or lipophilic portion of the formulation. Examples of suitable lipophilic thickeners include cetyl alcohol, stearyl alcohol, glyceryl stearate, white beeswax, microcrystalline wax, hydrogenated polyisobutylene polymers and emulsifying wax.

[0068] Other components

[0069] The composition of the present invention may be formulated with other components, such as fillers, carriers and excipients commonly found in cosmetic and pharmaceutical topical products. Other components include, but are not limited to, foaming agents, propellants, preservatives, antioxidants, sequestering agents, stabilizers, buffers, pH regulators, transdermal absorption enhancers, chelating agents, 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 inhibit changes in the particle size distribution of the composition during the shelf life. On a weight / weight basis, hexylene glycol can be added at 0.1% to 20%, on a weight / weight basis, preferably at 0.25% to 8%, and on a weight / weight basis, most preferably at 0.5% to 2%.

[0070] If desired, the preparation may contain other pharmaceutically acceptable excipients. For example, the preparation may contain a wetting agent such as glycerol, sorbitol, hexylene glycol, urea or propylene glycol. The preparation may contain an emollient such as vaseline, lanolin, mineral oil, light mineral oil, stearic acid, cyclomethicone or dimethicone. Other optional excipients include stabilizers, foaming agents, preservatives (such as methylparaben), pH adjusting agents (such as sodium hydroxide), chelating agents (such as EDTA and its salts) and buffers.

[0071] 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).

[0072] Other active agents

[0073] The compositions of the present invention can be formulated with other active agents depending on the condition to be treated. Other active agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, ketoprofen, naproxen), apremilast, JAK inhibitors (such as tofacitinib, ruxolitinib, oclacit), leukotriene inhibitors (such as zileuton, zafirlukast, montelukast), mast cell stabilizers (such as nedocromil, cromolyn sodium), leukotrienes (such as leukotrienes ... sodium, ketotifen, pemirolast), anthralin, azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfadiazine, mycophenolate mofetil, fumarate esters, corticosteroids (such as aclometasone, amcinonide, betamethasone, clobetasol, clocotolone, mometasone, triamcinolone, fluocinolone, fluocinonide, flurandrenolide, fluocinolone acetate, fluocinolone acetonide ... urandrenolide, diflorasone, desonide, desoximetasone, dexamethasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, prednicarbate, prednisone), adrenocorticotropic hormone, vitamin D analogs (such as calcipotriol, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, colchicine, bronchodilators (such as beta-agonists, anticholinergics, theophylline), and antibiotics (such as erythromycin, ciprofloxacin, metronidazole).

[0074] Administration and Dosage

[0075] 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.

[0076] The composition preferably contains roflumilast, a salt of roflumilast, an N-oxide of roflumilast 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. Topical preparations containing a PDE-4 inhibitor (such as roflumilast) are applied to the skin in an amount sufficient to obtain the desired pharmacological effect, which is generally to improve the signs and / or symptoms of a medical condition. The dosage of the preparation may vary depending on the PDE-4 inhibitor contained in the preparation, the concentration of the PDE-4 inhibitor in the preparation, and the frequency of application of the preparation. In general, the frequency of application of the preparation is from once a week to several times a day, preferably from every other day to three times a day, and most preferably once or twice a day.

[0077] Formulations containing PDE-4 inhibitors are useful in veterinary and human medicine to treat systemic medical conditions that are ameliorated by or responsive to systemic administration of a PDE-4 inhibitor such as roflumilast. Non-limiting examples of such medical conditions include, but are not limited to, acute and chronic airway disorders such as bronchitis, allergic bronchitis, asthma, and COPD; proliferative, inflammatory, and allergic skin diseases such as psoriasis, scalp psoriasis or inverse psoriasis, irritant and allergic contact eczema, hand eczema, atopic dermatitis, seborrheic dermatitis, lichen simplex, sunburn, mouth ulcers, lichen planus, vitiligo, pruritus of the genital or anal area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, microcystic and extensive abscesses, intrinsic and extrinsic acne, rosacea, disorders based on excessive release of TNF and leukotrienes, cardiac disorders treatable by PDE inhibitors, inflammation of the gastrointestinal system or central nervous system, ocular disorders, diseases treatable by the tissue relaxant effects of PDE inhibitors, and other proliferative, inflammatory, and allergic skin diseases; and immune-mediated diseases such as arthritis, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, and psoriatic arthritis.

[0078] Topical formulations containing PDE-4 inhibitors such as roflumilast can be prepared by processes commonly used in the field of making topical pharmaceutical formulations. In order to make a single-phase formulation, such as a liquid, the components of the formulation can be combined and mixed until a uniform solution or suspension of the active ingredient is obtained. In order to make a multi-phase formulation (such as an emulsion), the components of the aqueous phase and the oil phase can be combined and mixed separately until a uniform solution is obtained, and then the aqueous solution and the oil solution can be combined and mixed, such as by stirring to form a formulation. One or more pharmaceutically active ingredients can be dissolved (molecularly dispersed), complexed or associated with excipients or other active ingredients, or can be particulate (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 an elevated temperature of 50-90°C or at room temperature of 20-30°C, or at a temperature between room temperature and elevated temperature.

[0079] 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 of ordinary skill in the art.

[0080] In the following examples, roflumilast is used as a representative example of a PDE-4 inhibitor drug. In addition, in the following examples, Crodafos containing a phosphate surfactant, dicetyl phosphate and ceteth-10 phosphate TM CES (Croda Inc., Edison, NJ) was used as a representative example of a phosphate ester surfactant.

[0081] Example 1 - Formulations of the Invention and Prior Art

[0082] The first formulation of the present invention, hereinafter referred to as Formulation 1, was prepared by combining Roflumilast with a phosphate surfactant and water. The formulation was buffered with NaOH to obtain a pH of 6.5.

[0083] The second formulation of the present invention, hereinafter referred to as Formulation 2, was prepared by combining the above components and adding diethylene glycol monoethyl ether. The formulation was buffered with NaOH to obtain a pH value of 6.5.

[0084] A formulation not belonging to the present invention, hereinafter referred to as comparative formulation 3, was prepared by combining roflumilast with diethylene glycol monoethyl ether. The formulation was gelled with hydroxypropylcellulose to give it a viscosity and spreadability on the skin similar to the two phosphate surfactant emulsion formulations 1 and 2. The semisolid formulation was also buffered with NaOH to obtain a pH of 6.5.

[0085] The compositions of these preparations are shown in Table 1 below.

[0086] Table 1

[0087]

[0088] Example 2 - Single Dose Testing of the Formulation of Example 1

[0089] Order male and female pigs (Gottingen strain) (Marshall BioResources, NorthRose, NY) weighed 8-12 kg on arrival. Hair was clipped from the back of each animal one day before application of the topical cream semisolid formulation of Example 1 containing 0.15% roflumilast. The pigs were sedated during the shaving process. Care was taken to avoid abrasions of the skin.

[0090] Gently distribute one of the cream formulations of Example 1 to the shaved skin area at 2 grams per kg of pig body weight using a glass stirring rod or stainless steel spatula. Apply the cream evenly to form a thin, uniform film starting from the scapular area and moving to the caudal end of the test site. The width of the test site area is divided along both sides of the spine. Six pigs (3 males and 3 females) were administered a single dose of Formulation 2. Blood was drawn from the anterior vena cava (via thoracic access) or from other appropriate veins before dosing (time = 0) and 1, 2, 4, 8 and 24 hours after dosing. A one-week washout (no product intake) was sufficient to reduce plasma levels of roflumilast to zero, as verified by the pre-dose (time = 0) sample. After the washout period, a single dose of Formulation 1 was applied. After a second one-week washout period, a single dose of Formulation 3 was applied. The blood draw was identical for all three groups. The results are presented graphically in Figure 1 middle.

[0091] like Figure 1 As shown, pigs administered the prior art comparative formulation 3 exhibited a rapid spike to Cmax within 3 hours after administration. In contrast, pigs administered the present invention formulation 1 containing the phosphate ester surfactant Crodafos CES exhibited almost no spike to Cmax. Pigs administered the present invention formulation 2 containing both the phosphate ester surfactant and diethylene glycol monoethyl ether, like the pigs administered formulation 1, showed a reduced spike to Cmax compared to formulation 3. However, the Cmax obtained with formulation 2 was higher than that of formulation 1.

[0092] Figure 1The PK data results in the present invention show that the single-dose PK profile data of the preparation containing the phosphate surfactant lacks a significant spike to Cmax and has a low Cmax of 0.36ng / mL, while maintaining an average plasma concentration of 0.34ng / mL at the 4-hour sampling point. This is in contrast to the PK data of the DEGEE preparation, which rapidly rises to a Cmax of 0.85ng / mL within 2 hours and then also rapidly drops to 0.57ng / mL within 4 hours. When the phosphate surfactant is added to the DEGEE preparation of the present invention, it lacks a significant spike to Cmax and has a low Cmax while maintaining AUC, which is in contrast to the PK data of the DEGEE preparation without the phosphate surfactant. In view of the teaching of the prior art (Bolle): regardless of the components of the topical preparation, the Cmax and AUC of the topical preparation containing roflumilast are similar, and this PK data is particularly surprising. Contrary to what people expect based on the teaching of the prior art, the preparation 1 containing the phosphate surfactant lacks a significant spike to Cmax. In addition, the mean plasma concentration was maintained at 0.34 ng / mL throughout the 4-hour sampling points. In contrast, Formulation 3, which contained diethylene glycol monoethyl ether but lacked a phosphate surfactant, showed a rapid spike to a Cmax of 0.85 ng / mL within two hours. When a phosphate surfactant was used in conjunction with diethylene glycol monoethyl ether, administration of Formulation 2 did not produce a significant spike to Cmax and had a Cmax intermediate between Formulations 1 and 3 while maintaining AUC.

[0093] Example 3 - Formulations of the invention and closest prior art formulations

[0094] A third embodiment of the present invention, hereinafter referred to as Formulation 4, is prepared by combining roflumilast at a concentration of 0.3% w / w with a phosphate surfactant and water. The formulation is buffered with NaOH to obtain a pH of 5.5. The formulation is similar to Formulation 1, except that the concentration of roflumilast is 0.3% instead of 0.15%, and the emulsion is buffered to a pH of 5.5 instead of a pH of 6.5.

[0095] A formulation not belonging to the present invention, hereinafter referred to as comparative formulation 5, is prepared by combining a phosphate surfactant, a polyoxyethylene stearate surfactant and diethylene glycol monoethyl ether and other excipients with roflumilast at a concentration of 0.3%. The formulation is a cream formulation containing a commonly used phosphate surfactant other than Crodafos CES.

[0096] A formulation not belonging to the present invention, hereinafter referred to as comparative formulation 6, was prepared by combining roflumilast at a concentration of 0.2%. Said formulation is the closest prior art formulation known to the inventors and is disclosed in Example 3 of US Patent Application No. US2006 / 0084684 to Bollee et al.

[0097] The composition of the preparation is shown in Table 2 below.

[0098] Table 2

[0099]

[0100] *The exact ratio of cetearyl alcohol to dicetyl phosphate to ceteth-10 phosphate in Crodafos CES is consistent across batches but is not publicly disclosed by the manufacturer (Croda). The safety data sheet for Crodafos CES states that this emulsifier is composed of 60-80% cetearyl alcohol, 10-20% dicetyl phosphate, and 10-20% ceteth-10 phosphate. To emphasize the similarity of the components between Formulation 4 (phosphate surfactant blend) and Comparative Formulation 5 (phosphate and nonionic surfactant blend) and Comparative Formulation 6 (nonionic surfactant blend), the cetearyl alcohol portion of Crodafos CES is listed separately from the surfactant portion of Crodafos CES in Table 2.

[0101] Glyceryl Stearate / / PEG-100 Stearate is a term used by the U.S. Food and Drug Administration to describe 165 and Tego 150 is a term for a nonionic emulsifier blend sold under the trade name TRANSMIT®.

[0102] Medium chain triglycerides are a term used by the Food and Drug Administration to describe fatty acids that are used to 812 and A term for caprylic / capric triglyceride, a cosmetic ingredient sold under the trade name GTCC.

[0103] Example 4 - 14-day dosing test of the formulation of Example 3

[0104] Order male and female pigs (Gottingen The weight of the animals (strain) on arrival was 8-12 kg. The hair was clipped from the back of each animal one day before application of a topical cream semisolid formulation of Example 3. The pigs were sedated during the shaving process. Care was taken to avoid abrasions of the skin.

[0105] Gently distribute one of the cream formulations of Example 3 onto the clipped skin area at 2 grams per kg of pig body weight using a glass stirring rod or stainless steel spatula. Apply the cream evenly to form a thin, even film starting from the scapular area and moving to the caudal end of the test site. The width of the test site area is divided along both sides of the spine. The 18 pigs were divided into 3 groups of 6 pigs (3 males and 3 females) each, and each group of pigs was dosed with one of formulations 4, 5, or 6. Blood was drawn from the anterior vena cava (via thoracic access) or from other appropriate veins before dosing (time = 0) and 1, 2, 4, 8, and 24 hours after dosing. The results are presented in graphical form on Figure 2 middle.

[0106] like Figure 2 As shown, the pigs administered with the prior art formulation 5 showed a rapid spike to a Cmax value of 6.6 ng / mL within 1 hour after the 14th dose of continuous administration per day. In contrast, the pigs administered with the present invention formulation 4 containing the phosphate surfactant Crodafos CES showed almost no spike to the Cmax value.

[0107] The results are Figure 2 The steady-state PK profile data of the formulation of the present invention after 14 days of once-daily dosing lacks a significant spike to Cmax and has a low Cmax while maintaining AUC, which is in contrast to the PK data of the prior art formulations or formulations using phosphate ester surfactants other than Crodafos CES. These results are particularly surprising in view of the prior art (Bolle) teaching that the Cmax and AUC of topical formulations containing roflumilast are similar regardless of the components of the topical formulation.

[0108] Example 5 - Multiple-dose pharmacokinetic testing compared to prior art

[0109] The fourth formulation of the present invention is shown in Table 3, hereinafter referred to as Formulation 7, which is prepared into a complete formulation by combining the above components and adding diethylene glycol monoethyl ether and other components. The formulation is buffered with NaOH to obtain a pH value of 5.5. The qualitative and quantitative composition of Formulation 7 differs only in the amount of Roflumilast added to the cream. Because of the addition of a portion of 1% Roflumilast, a portion of 1% water is removed from the cream.

[0110] Table 3

[0111]

[0112] Order male and female pigs (Gottingen strain) weighed 8-12 kg on arrival. Hair was clipped from the back of each animal one day before application of the topical cream containing roflumilast. The pigs were sedated during the shaving process. Care was taken to avoid abrasions of the skin.

[0113] Gently distribute the cream formulation 7 with different concentrations of roflumilast to the shaved skin area in an amount of 2 grams per kg of pig body weight with a glass stirring rod or a stainless steel spatula. The cream was evenly applied to form a thin, uniform film starting from the shoulder 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. 20 pigs (10 males and 10 females) were administered 1% roflumilast cream, 12 pigs (6 males and 6 females) were administered 0.5% roflumilast cream, and 12 pigs (6 males and 6 females) were administered 0.15% roflumilast cream, once a day for 28 days. 6 pigs (3 males and 3 females) were administered 0.3% roflumilast cream (formulation 7) every day for 14 days. Blood was drawn from appropriate veins before dosing (time = 0) and at 1, 2, 4, 8, and 24 hours post-dose on days 1 and 28 (or day 14 for 0.3% roflumilast). The results are presented graphically in Figure 3 (0.15% roflumilast cream), Figure 4 (0.3% Roflumilast), Figure 5 (0.5% roflumilast cream) and Figure 6 (1.0% roflumilast cream) and are presented in table 4.

[0114] like Figures 3 to 6 As shown in each figure, a gradual increase to Cmax is evident from the pharmacokinetic profile on day 1. Figures 3 to 6 The most striking and surprising thing about the data presented is that in the pharmacokinetic profile on day 28 or day 14 (0.3% roflumilast cream), after reaching steady-state dosing, the blood concentration of the drug is in a very gentle and prolonged plateau after Cmax.

[0115] Table 4

[0116]

[0117] Likewise, the data in Table 4 show that when the formulation of the present invention is topically applied, each of the four concentrations of roflumilast has minimal variation in blood concentration between the trough and peak (Cmax) levels after reaching steady state.

[0118] Example 6 - Clinical Study on Subjects with Plaque Psoriasis

[0119] Study Design

[0120] ARQ-151 is a topical cream containing roflumilast. This Phase 1 / 2a clinical trial enrolled two cohorts: Cohort 1 evaluated a single application of ARQ-151 cream 0.5%, and Cohort 2 evaluated ARQ-151 cream 0.5% or 0.15% applied once daily for 28 days. In Cohort 1, subjects applied ARQ-151 cream 0.5% to 25 cm 2 Psoriatic plaques were treated in the clinic for 5-year follow-up. Subjects were screened (Visit 1), returned to the clinic for treatment (Visit 2) and PK blood draw, returned 24 hours after the baseline visit for a PK blood draw (Visit 3), and received a follow-up phone call 7 days after Visit 3 for safety assessment. Subjects who participated in Cohort 1 could participate in Cohort 2 if they met eligibility criteria; subjects who crossed over from Cohort 1 to Cohort 2 had all of their plaques up to 5% of their body surface area (BSA) treated in Cohort 2.

[0121] Cohort 2 was a parallel-group, double-blind, placebo-controlled study design. Subjects were randomized 1:1:1 to ARQ-151 cream 0.5%, ARQ-151 cream 0.15%, or matching placebo to be applied to all psoriasis plaques (except on the face, intercutaneous areas, scalp, palms, and soles) up to 5% BSA. Subjects in Cohort 2 had screening and baseline visits, follow-up visits at Weeks 1, 2, 3, and 4, an additional visit for final pharmacokinetic sample collection at Day 29, and a follow-up telephone call for safety assessments at Week 5.

[0122] Cohort 1 received open-label treatment without allocation or blinding. Assignment to treatment group in cohort 2 was by computer-generated randomization. Randomization was generated using SAS by an unblinded Premier Research statistician who was not otherwise involved in the conduct of the study. The block length was 3; a total of 72 blocks were used. Individuals were blinded to treatment.

[0123] This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The protocol was approved by the Research Review Board, Inc., Richmond Hill, ON, Canada for all sites. All subjects provided written informed consent before starting any specific study procedures. This trial is registered at ClinicalTrials.gov #NCT03392168.

[0124] Preparation of ARQ-151 Cream (Formulation 7)

[0125] Accurately weigh a target amount of 480 grams of Medical Sterile Water-USP into a 1000 ml glass beaker, then add 20 grams of Sodium Hydroxide Granular-NF and mix using a stir bar until completely dissolved. Set this solution aside and label it as 1N Sodium Hydroxide.

[0126] 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 using a propeller stirrer. This mixture was labeled the oil phase and was maintained at 75°C to 80°C.

[0127] In the main manufacturing vessel (20 L stainless steel vessel) add a target weight of 4225 grams of medical sterile water - USP and a target weight of 300 grams of 1N sodium hydroxide 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.

[0128] 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 stirrer until a clear and homogeneous solution was obtained. Sufficient potency-corrected roflumilast was added to the solution to obtain a 0.15% roflumilast cream or a 0.5% roflumilast cream, which was marked as the API phase.

[0129] 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 container and mix with a homogenizer until a smooth and uniform cream is obtained. Cool the cream to 45°C to 50°C using a propeller stirrer for mixing. Slowly add the API phase to the cream in the main manufacturing container 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 / v) dilute hydrochloric acid-NF. After the product to be packaged is released, pack the cream into aluminum 3 / 4" x 3 3 / 4" #16 seal in white tube and press the tube together to provide the primary container closure system.

[0130] patient

[0131] To be eligible for inclusion in Cohort 1, subjects had to be ≥18 years of age and have a ≥25 cm 2To be eligible for inclusion in Cohort 2, subjects must also have chronic plaque psoriasis of ≥6 months duration covering 0.5% to 5.0% of total BSA excluding the face, scalp, intercutaneous areas, palms, and soles. Subjects need to have at least 1 (and up to 3) target plaques with an area ≥9 cm 2 , Target Plaque Severity Score (TPSS) ≥ 4. Target plaques could be located anywhere on the body (excluding the face, scalp, intercutaneous areas, palms, and soles), including knees and elbows. Major exclusion criteria included: non-plaque psoriasis, drug-induced psoriasis, skin conditions that would affect study assessments, known hypersensitivity to excipients in ARQ-151 emulsion, hypersensitivity to PDE-4 inhibitors, inability to discontinue use of strong P-450 cytochrome inducers or P-450 cytochrome inhibitors, inability to avoid tanning bed use, inability to discontinue systemic or topical therapy for psoriasis, active infection within 7 days of baseline requiring oral or intravenous antibiotics, antifungal, or antiviral medications, or a history of cancer within 5 years, except for completely resected basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical cancer.

[0132] Treatment and Application

[0133] Formulation 7, also known as ARQ-151 cream, contained either 0.5% or 0.15% roflumilast. The vehicle group contained all components of ARQ-151 cream except roflumilast. In cohort 1, ARQ-151 cream 0.5% was applied clinically to 25 cm 2 In cohort 2, all psoriasis lesions up to 5% BSA (except lesions on the face, scalp, intercutaneous areas, palms, and soles) were treated by subjects at home. Investigators instructed subjects on the correct dosing and application of ARQ-151 cream and vehicle groups.

[0134] Research Assessment

[0135] Efficacy (cohort 2 only), pharmacokinetics (both cohorts), and safety (both cohorts) were assessed. The primary and secondary efficacy endpoints were calculated based on the product of the target plaque severity score (TPSS) and the target plaque area (TPA). The TPSS for each plaque in each subject was determined as the sum of erythema, induration, and scaling, with each score scored on a scale of 0 (none) to 4 (very severe), the same severity score used in the PASI. TPA (cm 2) is determined by multiplying the longest diameter (cm) by the widest perpendicular diameter (cm) of the target plaque. Therefore, the product of TPSS x TPA is roughly analogous to the PASI of the treated plaque. TPSS and TPA assessments were performed at Screening, Baseline, and Weeks 1, 2, 3, and 4. Elective photography was performed at the 4 midpoints at Baseline and Visits 2, 3, 4, and 6.

[0136] The pharmacokinetic profiles of roflumilast and its active metabolite, roflumilast N-oxide 12, were determined from plasma. Blood was drawn for pharmacokinetic analysis at 1, 2, 4, and 6 hours after ARQ-151 administration on Day 1. On Day 28, samples were drawn before dosing (trough level) and at 1, 2, 4, 6, and 24 hours after dosing.

[0137] Safety endpoints included the type and incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs); application site reactions; and changes in physical examination, vital signs, electrocardiograms, and clinical laboratory parameters. Safety was assessed at all study visits and telephone follow-up. Skin irritation was assessed on Days 1 and 2 for Cohort 1 and at baseline and Visits 3, 4, 5, and 6 for Cohort 2. Skin irritation was assessed using a scale developed by Berger and Bowman13, ranging from 0 (no evidence of irritation) to 7 (strong reaction spreading beyond the application site). In addition, other clinical signs of irritation were scored on a scale ranging from "A" (mild shiny skin surface) to "F" (small macular erosions and / or crusts). Another safety endpoint was the results of the Depression Symptoms Questionnaire14, which was administered at screening, Week 2, and Week 4. The questionnaire is a 16-item depression symptom assessment scale with scores for each item ranging from 0 to 3. The severity of depression was based on scoring categories, where a total score of ≤5 represented no depression; 6-10 represented mild depression; 11-15 represented moderate depression; 16-20 represented severe depression; and ≥21 represented very severe depression.

[0138] Statistical considerations

[0139] For Cohort 2, a sample size of 24 subjects per group (72 subjects total) was estimated to provide 80% power to detect a 23% difference in the mean percentage change from baseline in the primary endpoint between the ARQ-151 cream and matched vehicle groups. The estimate was based on a one-way ANOVA with an α=0.025 significance level. To accommodate a 16% dropout rate, the total sample size was increased to 84 subjects.

[0140] TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 20.1, and severity was rated on a 5-level scale of Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening consequences), or Grade 5 (death related to the AE).

[0141] Pharmacokinetic parameters were calculated using the plasma concentration values ​​(ng / mL) of roflumilast and roflumilast N-oxide at each nominal time point using Phoenix WinNonlin (v8.0) using standard noncompartmental analysis. The area under the concentration-time curve (AUC) was estimated using linear trapezoidal linear interpolation. Maximum plasma concentration (Cmax) and time to reach maximum concentration (Tmax) were based on direct assessment. Reported sample concentration values ​​below the limit of quantification (BLQ; <0.100 ng / mL) were ignored.

[0142] The primary efficacy endpoint was the mean percentage difference in the TPSS×TPA product from baseline at week 4 between each dose of ARQ-151 cream and vehicle control. The primary efficacy endpoint was analyzed with a mixed model for repeated measures, with country, treatment, study visit, and treatment-by-study-visit interaction centered as fixed effects, and baseline TPSS×TPA score as a covariate. The mean difference from baseline was calculated for each treatment visit. The mean percentage change from baseline for each ARQ-151 dose and the corresponding vehicle group was compared using an unstructured covariance structure unless the model did not converge; in this case, an appropriate covariance structure was investigated. The Bonferroni method was used to control for multiplicity, with an α=0.025 significance level for each pairwise comparison of the active ingredient with placebo.

[0143] Secondary efficacy endpoints included the mean percentage difference in TPSS×TPA composite score, TPSS, and TPA between each dose of ARQ-151 cream and vehicle control at Weeks 1, 2, and 3. Statistical analyses for secondary efficacy endpoints were identical to those used for the primary endpoint, except that no multiplicity correction was used and all analyses were performed at the α=0.05 level.

[0144] In a post hoc analysis, the percentages of subjects with a 75% and 90% improvement from baseline in TPSS×TPA at each study visit at Week 4 (75% responders and 90% responders) were also evaluated.

[0145] Safety analyses were performed in the safety population, which included all subjects who received at least 1 dose of study drug and based on treatment received. Pharmacokinetic analyses were performed on the pharmacokinetic population, which included all subjects who consented to sampling and received active drug with roflumilast in plasma concentrations sufficient to define a profile. Efficacy analyses were performed in the modified intention-to-treat population, which consisted of all subjects in Cohort 2 who received ≥1 dose of study drug and had ≥1 post-baseline efficacy assessment.

[0146] No imputation was performed for missing data. Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and graphical presentation (except for PK parameter estimates) were performed primarily using SAS (version 9.4). All PK parameter estimates were performed using Version 6.4 or later.

[0147] result

[0148] patient

[0149] Subjects were recruited from 7 study sites in Canada and 1 site in the United States between December 5, 2017 (first enrolled patient) and May 2, 2018 (last follow-up visit). Eight subjects participated in Cohort 1 and 89 subjects participated in Cohort 2, which included subjects randomized to ARQ-151 cream 0.5% (N=30), ARQ-151 cream 0.15% (N=28), and vehicle (N=31). All subjects in Cohort 1 received treatment and completed the study, and 6 also participated in Cohort 2. Four subjects in Cohort 2 discontinued the study prematurely due to no follow-up (n=3) or other reasons (n=1). There were no discontinuations due to AEs. The safety population included all 8 subjects in Cohort 1 and all 89 subjects in Cohort 2. The PK population included 20 subjects who received Formulation 7 (ARQ-151 cream) 0.5% and 22 subjects who received Formulation 7 (ARQ-151 cream) 0.15%. The efficacy population included all subjects in Cohort 2.

[0150] The mean age (standard deviation [SD]) was 51.6 (16.9) years in cohort 1 and ranged from 47.5 to 55.3 years across treatment groups in cohort 2 (Table 5). Most subjects were white. The mean BSA involved was ∼2% across all treatment groups. Of the 89 subjects in cohort 2, 35 (39.3%) had target plaques located above the knee, elbow, or both.

[0151] Table 5 Characteristics of subjects (safety population)

[0152]

[0153] BSA, body surface area; NC, not collected; SD, standard deviation.

[0154] Effectiveness Results

[0155] The primary efficacy endpoint was achieved: the mean percentage change from baseline in TPSS×TPA at Week 4 was significantly different for ARQ-151 cream 0.5% (P=0.0007) and ARQ-151 cream 0.15% (P=0.0011) compared to vehicle (Figure 7A). For both concentrations of ARQ-151 cream, the primary endpoint improved by 66%-67% from baseline after 4 weeks of treatment, compared to 38% for vehicle, based on the mean percentage change from baseline by least squares (LS). Both drug product concentrations achieved statistical separation from vehicle as early as Week 2 of treatment, and drug product differences from vehicle continued to increase through Week 4. Formulation 7, ARQ-151 cream 0.5% and 0.15%, showed similar efficacy for the primary endpoint throughout the study period.

[0156] The secondary efficacy endpoints of change from baseline in TPSS ( FIG. 7B ) and change from baseline in TPA ( FIG. 7C ) were statistically significantly different between the two active concentrations of ARQ-151 and the vehicle group after 4 weeks of treatment. Change from baseline in TPSS, but not TPA, reached statistical significance as early as 2 weeks for both active concentrations of ARQ-151 compared to the vehicle group.

[0157] After 4 weeks of treatment, patients receiving Formulation 7, ARQ-151 cream 0.5% and 0.15%, and vehicle had their TPSS x TPA scores compared to baseline. Of note, subjects treated with vehicle appeared to have improvements primarily in the appearance of scaling (as would be expected for an emollient cream). Subjects receiving ARQ-151 cream 0.5% and 0.15% both showed instances of substantial improvement in treatment-resistant areas of psoriasis, the elbows or knees. In fact, 39.3% of subjects had target plaques on the elbows and / or knees.

[0158] In a post hoc analysis, the 75% response rate (TPSS×TPA 75% improvement from baseline) at Week 4 was also assessed. In the ARQ-151 cream 0.5% group, 10 subjects (35.7%) achieved this level of improvement (P=0.0090), and in the ARQ-151 cream 0.15% group, 7 subjects (25.9%) were 75% responded (P=0.0700). There were two 75% responders in the vehicle group. In the same analysis, the 90% response rate at Week 4 was also assessed. In the ARQ-151 cream 0.5% group, 4 subjects (14.3%) achieved this level of improvement, and in the ARQ-151 cream 0.15% group, 3 subjects (11.1%) were 90% responded; however, neither 90% response rate was statistically significant. There was one 90% responder in the vehicle group.

[0159] Pharmacokinetic results

[0160] In cohort 1, for 25 cm 2 Limited evidence of systemic plasma exposure of roflumilast or roflumilast N-oxide was observed after a single topical application of ARQ-151 0.5% to psoriatic plaques covered with 0.5% to 5% BSA in cohort 2 (data not shown). Systemic plasma exposure of roflumilast and roflumilast N-oxide was observed after single or multiple applications of Formulation 7 (ARQ-151) to psoriatic plaques covered with 0.5% to 5% BSA in cohort 2 (Table 8, Fig. 8A 0.5% Formulation 7, ARQ-151 cream, Figure 8B 0.15% Formulation 7, ARQ-151 cream). On day 1, the exposure of roflumilast but not roflumilast N-oxide showed an increase in a dose-dependent manner. On day 28, the plasma concentration vs time profile was relatively flat (with very small peak-to-trough differences), indicating that the exposure of roflumilast and roflumilast N-oxide reached a steady state and showed an increase in a dose-dependent manner. The ratio of N-oxide to roflumilast after topical application ranged from 4.7 to 5.9, which was 12 after oral administration of roflumilast, which was higher due to an increased contribution of first-pass metabolism.

[0161] like Fig. 8A and 8B As shown in Figure 2, when roflumilast was formulated in a cream containing the phosphate surfactant Crodafos CES, it showed a clear gradual rise to Cmax in both single-dose and steady-state pharmacokinetic profiles. Fig. 8A and 8BAs shown, within 24 hours after the first application of 0.15% or 0.5% Formulation 7 (ARQ-151 cream) to human subjects, the drug plasma concentration after Cmax has a very gentle and long plateau. After Formulation 7 is administered to the skin, the pharmacokinetic profile of roflumilast has the same shape of low rise to Cmax when applied to humans or pigs.

[0162] Table 6 Pharmacokinetic parameters (pharmacokinetics population; cohort 2)

[0163]

[0164]

[0165] AUC 0-last , until the area under the concentration-time curve at the last measurable time point; C max , maximum plasma concentration; T max , time to reach maximum plasma concentration.

[0166] Safety Results

[0167] In cohort 1, only 1 subject reported a TEAE, which was considered unrelated to treatment (Table 9). In cohort 2, the percentage of TEAEs in the 0.15% group was lower than that in the 0.5% or vehicle groups (the percentage of treatment-related TEAEs was 7.1% vs 23.3% and 25.8%, respectively; and the percentage of all TEAEs was 25% vs 40% and 35.5%, respectively) (Table 9); all TEAEs were mild or moderate in severity. No SAEs were reported in this study, and no subject discontinued the study due to TEAEs. All treatment-related TEAEs were related to the application site, a total of 17 cases. TEAEs at the application site were generally mild in severity and number (16 cases were mild and 1 case was moderate), and no consistent differences were shown between the drug product and vehicle groups. No changes in physical examination, vital signs, electrocardiograms, or clinical laboratory parameters were considered clinically significant. There were no clinically significant differences in weight changes between treatment groups. One subject in the 0.5% treatment group reported one episode of moderate nausea, which did not recur during the remaining 3 weeks of the study. No subject reported vomiting or diarrhea. No signs of skin irritation (skin reactions) were found in Cohort 1. For Cohort 2, the mean (SD) skin reaction scores for ARQ-151 cream 0.5%, 0.15%, and vehicle groups at baseline were 0.2 (0.5), 0.0 (0.2), and 0.2 (0.4), respectively, and at Week 4 were 0.1 (0.5), 0.0 (0.0), and 0.1 (0.4), respectively.

[0168] Table 7 Safety Summary (Safety Population)

[0169]

[0170]

[0171] SAE, serious adverse event; TEAE, treatment-emergent adverse event.

[0172] discuss

[0173] In this Phase 1 / 2a clinical trial, Formulation 7 (ARQ-151 Cream) 0.5% and 0.15% were well tolerated, safe, and effective for the treatment of chronic plaque psoriasis. Formulation 7 (ARQ-151 Cream) demonstrated strong efficacy at both doses tested, as evidenced by statistically significant reductions in plaque severity and size compared to the vehicle group.

[0174] Statistically significant efficacy of ARQ-151 (Formulation 7 containing either 0.15% or 0.5% roflumilast) versus vehicle was observed for both active doses at the primary study endpoint 2 weeks after initiation of treatment, and the difference between ARQ-151 and vehicle continued to increase at the final visit at 4 weeks. Mean TPSS×TPA values ​​for the LS decreased by 38% over the vehicle group throughout the study; this efficacy advantage occurred primarily in the first week of treatment, which may have been contributed by the reduced scaling that was apparent to the observer's eye as a result of the emollient cream. At week 4, there was no difference in efficacy between ARQ-151 cream 0.5% and 0.15% for the primary endpoint (percent change from baseline in TPSS×TPA). However, the 75% remission rate at week 4 suggests that the 0.5% cream (35.7%; P=0.0090 versus vehicle) was slightly more effective than the 0.15% concentration (25.9%; P=0.0700). After 4 weeks of dosing with both active drug concentrations, TPSS×TPA values ​​had decreased by 66%-67% from baseline based on LS means. However, TPSS×TPA did not plateau in ARQ-151-treated subjects, suggesting that longer treatment durations may provide greater efficacy.

[0175] The TPSS × TPA endpoint was chosen to be similar to the systemic Psoriasis Area and Severity Index (PASI) measurement. Both use the same plaque severity scale, which in the current study was applied to 1–3 target lesions, compared with the systemic PASI. The “area” function of TPA differs from the PASI’s assessment of plaque area involvement, but we propose that the product of TPSS × TPA provides a similar assessment of “target plaques” as the systemic PASI. Based on this hypothesis, the efficacy of topical ARQ-151 after 4 weeks of dosing (35.7% of subjects in the 0.5% cream group achieved 75% improvement) may be similar to that of the systemic PASI. This is comparable to the class 1 steroid betamethasone dipropionate 0.064% in a phase 3 study of (32.7% PASI 75 response rate after 4 weeks of dosing).

[0176] The safety profile of Formulation 7 (ARQ-151 cream) at 0.5% and 0.15% was similar to that of the vehicle group, which can be explained at least in part by pharmacokinetics. When administered orally for the treatment of COPD, roflumilast may be associated with gastrointestinal side effects (diarrhea, nausea), headache, and weight loss in a minority of patients. Typically, clinical development of oral PDE-4 inhibitors is limited by gastrointestinal effects such as nausea and vomiting. In fact, nausea, vomiting, and weight loss are thought to be mediated at the brain level. In contrast to oral administration, in our study, topical administration of roflumilast was associated with a slow rise to maximum plasma concentrations over many days, and exposure to roflumilast and its active metabolite, roflumilast N-oxide, was flat throughout the dosing period (i.e., C of the dosing interval). max ~C min ). Nausea and vomiting were not observed in this study, possibly due to the lack of “peak to trough” Cmax variation; lower Cmax values ​​than observed after oral administration; or bypassing of the gastrointestinal tract when administered topically.

[0177] PDE-4 inhibition represents an effective mechanism of action for oral psoriasis treatments, but is a novel mechanism of action for topical psoriasis treatments. Patients with mild to moderate disease make up the majority of the psoriasis patient population. This patient population has not benefited from the recently introduced biologic therapies for patients with more severe disease. However, it is not surprising that PDE-4 inhibition is an effective modality for treating psoriasis. In 2014, apremilast was approved for oral treatment of psoriasis. Clisborole is currently approved for the treatment of atopic dermatitis at a concentration of 2%. Roflumilast is a highly potent PDE-4 inhibitor that exhibits half maximal inhibitory concentration (IC50) values ​​for roflumilast and roflumilast N-oxide at subnanomolar potency against different PDE-4 isomers and isoforms. Roflumilast is 50-300 times more potent than apremilast or crisaborole against different PDE-4 isomers and isoforms. The oral dose of roflumilast, only 0.5 mg per day, reflects this extremely high potency.

[0178] Example 7 - Single-dose and multiple-dose human pharmacokinetic study of crisaborole

[0179] As According to the package insert (Pfizer Labs, New York, NY), the 2% PDE4 inhibitor crisaborole is formulated as a topical ointment consisting of white petrolatum, propylene glycol, mono- and di-glycerol, paraffin, butylated hydroxytoluene, and calcium disodium EDTA. The formulation does not contain a phosphate ester surfactant.

[0180] Apply once daily in patients with atopic dermatitis who have 25% or greater body surface area of ​​affected skin Ointment. Published in the non-confidential section of the Summary Basis of Approval (SBOA) The pharmacokinetics of a single dose (day 1) of crisaborole, the active ingredient in the PDE4 inhibitor, in Fig. 9 For the same patients, once daily use On day 8 of treatment, steady-state pharmacokinetic data of crisaborole were obtained. SBOA obtains and Fig. 9 As shown, the PDE4 inhibitor crisaborole, when administered from a commercial topical ointment, rapidly rises to a peak Cmax within 4 hours and then declines to near pre-dose levels within 24 hours of once-daily dosing. This high Cmax peak of the PDE4 inhibitor occurs after steady-state dosing with both a single topical application and once-daily ointment application.

[0181] Example 8 - Comparison of Single-Dose Pharmacokinetics of Crisborole Delivered in Crodafos CES Cream and Roflumilast Delivered in the Same Cream

[0182] Clisborole (0.3% w / w) was formulated into a cream formulation 8 by combining Crodafos CES (a commercial blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate), diethylene glycol monoethyl ether, and other components to create a complete commercial formulation. Formulation 8 has the same excipients in the same proportions as formulation 7 of the present invention. The only difference between the two formulations is that formulation 8 contains 0.3% crisaborole as a PDE-4 inhibitor pharmaceutically active ingredient, while formulation 7 contains 0.3% roflumilast as a PDE-4 inhibitor pharmaceutically active ingredient. Both formulations were buffered with NaOH to obtain a pH of 5.5.

[0183] Table 8

[0184]

[0185] Order male and female pigs (Gottingen strain) weighed 8-12 kg on arrival. Hair was clipped from the back of each animal one day before application of the topical cream containing roflumilast. The pigs were sedated during the shaving process. Care was taken to avoid abrasions of the skin.

[0186] Gently distribute cream Formulation 8 (containing 0.3% crisaborole) to the clipped skin area at 2 grams per kg of pig body weight using a glass stirring rod or stainless steel spatula. Apply the cream evenly to form a thin, even film starting from the scapular area and moving to the caudal end of the test site. The width of the test site area is divided along both sides of the spine. Twelve pigs (6 males and 6 females) were administered 0.3% crisaborole cream (Formulation 8) once. Six pigs (3 males and 3 females) were administered 0.3% roflumilast (Formulation 7) once. Blood was drawn from an appropriate vein prior to dosing (time = 0), and 1, 2, 4, 8, and 24 hours after dosing. The single-dose results for the two PDE-4 inhibitors are presented graphically in Fig.10 .

[0187] like Fig.10 As shown, when the PDE-4 inhibitor is formulated in a cream containing the phosphate surfactant Crodafos CES, a gradual rise to Cmax is clearly visible in the single-dose pharmacokinetic profile. Fig.10 The most striking and surprising aspect of the data presented in the present study is that within 24 hours after the first application of crisaborole 0.3% cream in pigs, the blood concentration of the drug had a very gentle and prolonged plateau after Cmax. The pharmacokinetic profiles of the PDE4 inhibitors roflumilast and crisaborole had the same shape of low rise to Cmax when delivered by the same Crodafos CES cream formulation. This PK profile of low rise to Cmax was not present when the topical formulations of roflumilast or crisaborole were applied topically in a formulation without Crodafos CES.

[0188] Further modifications, uses and applications of the present invention will be apparent to those skilled in the art. Similar modifications are intended to be covered by the following claims.

Claims

1. A method of reducing gastrointestinal side effects in a patient who suffers from or is at risk of suffering from gastrointestinal side effects as a result of administration of a PDE-4 inhibitor drug, the method comprising administering to the patient a composition comprising a PDE-4 inhibitor drug in combination with a phosphate ester surfactant, the PDE-4 inhibitor drug being present at a concentration sufficient to provide a systemic effect of the drug, the phosphate ester surfactant comprising cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

2. The method of claim 1, wherein the composition is administered topically.

3. The method of claim 1, wherein the PDE-4 inhibitor drug is selected from the group consisting of apremilast, cilomilast, crisaborole, ibudilast, piramilalast, roflumilast, and rolipram.

4. The method of claim 3, wherein the PDE-4 inhibitor drug is roflumilast.

5. The method of claim 1, wherein the composition is in the form of a semisolid.

6. The method of claim 1, wherein the composition further comprises diethylene glycol monoethyl ether.

7. The method of claim 4, wherein the amount of roflumilast is 0.005-2% w / w.

8. The method of claim 7, wherein the amount of roflumilast is 0.05-1% w / w.

9. The method of claim 8, wherein the amount of roflumilast is 0.1-0.5% w / w.

10. The method of claim 3, wherein the amount of roflumilast is 0.3% w / w.

11. The method of claim 1, wherein the 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.

12. The method of claim 1, wherein the roflumilast composition further comprises at least one other component selected from the group consisting of solvents, humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH adjusting fluids, transdermal absorption enhancers, film formers, dyes, pigments, and fragrances.

13. The method of claim 1, wherein the roflumilast composition further comprises an additional active agent selected from the group consisting of a nonsteroidal anti-inflammatory drug (NSAID), apremilast, a JAK inhibitor, a leukotriene inhibitor, a mast cell stabilizer, anthralin, azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfadiazine, mycophenolate mofetil, fumarate esters, corticosteroids, corticotropin, vitamin D analogs, acitretin, tazarotene, cyclosporine, resorcinol, colchicine, a bronchodilator, and an antibiotic.

14. The method of claim 1, wherein the patient suffers from asthma or chronic obstructive pulmonary disease (COPD).

15. The method of claim 1, wherein the patient suffers from an inflammatory condition.

16. The method of claim 13, wherein the patient suffers from atopic dermatitis.

17. The method of claim 1, wherein the composition is administered in a semisolid or liquid form.

18. The method of claim 17, wherein the composition is administered in a form selected from the group consisting of an emulsion, a suspension, an ointment, an oil, a cream, a gel, a paste, a transdermal patch, a spray, and a foam.

19. The method of claim 18, wherein the composition is administered in the form of a foam.

20. A method of reducing a Cmax spike resulting from administration of a PDE-4 inhibitor drug comprising administering to the patient a composition comprising a PDE-4 inhibitor drug in combination with a phosphate ester surfactant at a concentration sufficient to provide a systemic effect of the drug, wherein the phosphate ester surfactant comprises cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

21. A composition comprising a PDE-4 inhibitor drug in combination with a phosphate ester surfactant comprising cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

22. The composition of claim 21, wherein the composition is in a form selected from the group consisting of an emulsion, a suspension, an ointment, an oil, a cream, a gel, a paste, a transdermal patch, a spray, and a foam.

23. The method of claim 22, wherein the composition is in the form of a cream or a foam.

Images