Self-preserving topical pharmaceutical composition containing diethylene glycol monoethyl ether

Abstract

The self-preserving topical pharmaceutical composition comprises diethylene glycol monoethyl ether (DEGEE) maintained at an acidic pH. The pH of the formulation can be maintained at a pH below 6.3, alternatively below 6.0. The topical pharmaceutical composition disclosed herein is self-preserving and can meet the European Pharmacopoeia Criterion A for antimicrobial preservative effectiveness without the addition of traditional antimicrobial preservatives. Certain pharmaceutical compositions further comprise an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, which is manufactured by Croda under the trade name Crodafos™ CES.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 319,586, filed March 14, 2022, and U.S. Provisional Patent Application No. 63 / 370,143, filed August 2, 2022, both of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION

[0002] The subject matter disclosed herein relates generally to topical pharmaceutical compositions. As disclosed herein, the present inventors have made the surprising discovery that topical pharmaceutical compositions comprising diethylene glycol monoethyl ether (DEGEE) maintained at an acidic pH are fully preserved without the addition of traditional antimicrobial preservatives. In preferred embodiments, the pharmaceutical composition is maintained at a pH of less than about 6.3, alternatively less than about 6.0. In preferred embodiments, the pharmaceutical composition further comprises an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, manufactured by Croda under the trade name Crodafos™ CES or Crodafos™ CES PHARMA. [Background technology]

[0003] Background of the Invention

[0003] Topical and transdermal drug delivery have various advantages over other routes of administration. Topical and transdermal delivery can be used to continuously deliver drugs to the systemic circulation and avoid first-pass metabolism. In contrast, oral drug delivery has a significant first-pass effect in the liver, which can prematurely metabolize drugs. Topical and transdermal delivery also has advantages over intravenous administration. Intravenous administration requires sterile products and is painful, which can increase patient noncompliance. On the other hand, topical and transdermal delivery is non-sterile, non-invasive, and can be self-administered.

[0004] Most topical products are nonsterile dosage forms packaged in multi-dose containers. The antimicrobial effectiveness test first appeared in the 18th Revision of the United States Pharmacopeia, which became official on September 1, 1970. This chapter was intended as a guide for product development scientists on how to evaluate the performance of antimicrobial agents added to inhibit the growth of microorganisms that may be introduced during or after the manufacturing process. Topical pharmaceutical preparations rarely contain enough alcohol (ethanol or isopropyl alcohol) to create a formulation with adequate antimicrobial activity to prevent the growth of microorganisms that may enter the product. For this reason, aqueous preparations, in particular, require the addition of antimicrobial preservatives to prevent microbial growth after contamination during manufacturing or to limit microbial contamination that may occur during normal storage and use conditions from multi-dose containers. If microbial growth is not limited by the topical preparation itself or by the addition of preservatives, this creates the potential for patient endangerment through infection and the potential for spoilage of the preparation. 21 Code of Federal Regulations, Part 211.113(a) (2008) states that "[a]ppropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed."

[0005]

[0005] An antimicrobial preservative is defined as a substance added to a non-sterile dosage form to protect it from microbial growth or from microorganisms accidentally introduced during or after the manufacturing process. Benzyl alcohol, phenoxyethanol, methylparaben, and propylparaben are typical examples of antimicrobial preservatives used in topical products. Antimicrobial preservatives are not used as a substitute for good manufacturing practice, nor are they used solely to reduce the viable microbial count of a non-sterile product. All useful antimicrobials are toxic substances. To maximize patient protection, the preservative concentration must be below a level that may be toxic to humans. Because different multi-dose containers pose different degrees of risk of patient contamination, the preservative concentration can be linked to the specific packaging. For example, the risk of microbial contamination is much higher for cream remaining in a wide-mouth jar when repeatedly "dipping" a finger into the jar compared to the same cream packaged in a tube with a small opening through which the cream is dispensed.

[0006]

[0006] Antimicrobial efficacy, whether inherent in the product itself or achieved through the addition of an antimicrobial preservative, must be established for all multi-dose topical dosage forms using written procedures. Furthermore, the concentration of preservative required to pass the Antimicrobial Effectiveness Test ("AET") must be minimized, and the AET must be performed on the final product container. A further general consideration for antimicrobial preservative testing is understanding that the effectiveness of the antimicrobial preservative may be enhanced or diminished by the active ingredient(s) of the preparation, the formulation incorporated, or the container and closure used. The antimicrobial activity of the preparation in the final container is investigated over its shelf life to ensure that such activity is not impaired by storage. Such investigations may be performed on samples removed from the final container immediately prior to testing. During the development of pharmaceutical preparations, it must be demonstrated that the antimicrobial activity of the preparation itself, or with the addition of an appropriate preservative or preservatives, as necessary, adequately protects the preparation from the deleterious effects that may result from microbial contamination or growth during storage and use. Therefore, the AET is considered a development test and not one that is routinely used to determine the quality of a final product. It is not routinely performed on individual products, but the product, when tested, is expected to meet the requirements over its shelf life. Summary of the Invention

[0007] The present invention relates to topical pharmaceutical compositions containing diethylene glycol monoethyl ether (DEGEE). The inventors have made the surprising discovery that topical pharmaceutical compositions containing diethylene glycol monoethyl ether (DEGEE) maintained at an acidic pH are fully preserved without the addition of conventional antimicrobial preservatives. In a preferred embodiment, the pharmaceutical composition is maintained at a pH of less than about 6.3, alternatively less than about 6.0. In a preferred embodiment, the pharmaceutical composition further comprises an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, manufactured by Croda under the trade name Crodafos™ CES or Crodafos™ CES PHARMA.

[0008] In certain embodiments, the present invention relates to a topical pharmaceutical composition comprising a pharmaceutically effective amount of an active ingredient, diethylene glycol monoethyl ether, and water. The topical pharmaceutical composition has a pH of 6.3 or less, or alternatively, 6.0 or less. In certain embodiments, the pharmaceutical composition has a pH of 5.0 to 6.3, or alternatively, a pH of 5.0 to 6.0.

[0009]

[0009] In certain embodiments, the pharmaceutical composition is a cream or gel.

[0010] In certain embodiments, the pharmaceutical composition meets the European Pharmacopoeia's Criterion A for Efficacy of Antimicrobial Preservation and / or the United States Pharmacopoeia ("USP") criteria for Category 2 (topical) products. The pharmaceutical composition can meet the European Pharmacopoeia's Criterion A for Efficacy of Antimicrobial Preservation and / or the USP criteria for Category 2 products even though the formulation does not contain an antimicrobial preservative. In certain embodiments, the pharmaceutical composition does not contain a conventional antimicrobial preservative, such as benzyl alcohol, parabens (e.g., methylparaben, ethylparaben, propylparaben, and butylparaben), phenoxyethanol, propylene glycol, bronopol, benzylkonium chloride, or benzethonium chloride.

[0010]

[0011] In certain embodiments, the pharmaceutical composition comprises about 10% to about 40% w / w diethylene glycol monoethyl ether, hi certain embodiments, the pharmaceutical composition comprises about 20% to about 35% w / w diethylene glycol monoethyl ether.

[0011]

[0012] In certain embodiments, the pharmaceutical composition further comprises an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, hi certain embodiments, the pharmaceutical composition comprises about 8% to about 15% w / w of an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

[0012]

[0013] In certain embodiments, the active ingredient is a poorly water-soluble drug, hi certain embodiments, the active ingredient is roflumilast.

[0014] In certain embodiments, the present invention relates to a topical pharmaceutical composition comprising a pharmaceutically effective amount of an active ingredient, an emulsifier blend of diethylene glycol monoethyl ether, cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, and water. In certain embodiments, the topical pharmaceutical composition has a pH of 6.3 or less, or alternatively, 6.0 or less. In certain embodiments, the pharmaceutical composition has a pH of 5.0 to 6.0, or alternatively, a pH of 5.0 to 6.3.

[0013]

[0015] In certain embodiments, the pharmaceutical composition is a cream or gel.

[0016] In certain embodiments, the pharmaceutical composition meets the European Pharmacopoeia Criterion A for antimicrobial preservative effectiveness and / or the USP Criterion for Category 2 (topical) products. The pharmaceutical composition can meet the European Pharmacopoeia Criterion A for antimicrobial preservative effectiveness and / or the USP Criterion for Category 2 products even though the formulation does not contain an antimicrobial preservative. In certain embodiments, the pharmaceutical composition does not contain a conventional antimicrobial preservative, such as benzyl alcohol, parabens (e.g., methylparaben, ethylparaben, propylparaben, and butylparaben), phenoxyethanol, propylene glycol, bronopol, benzylkonium chloride, or benzethonium chloride.

[0014]

[0017] In certain embodiments, the pharmaceutical composition comprises about 10% to about 40% w / w diethylene glycol monoethyl ether. In certain embodiments, the pharmaceutical composition comprises about 20% to about 35% w / w diethylene glycol monoethyl ether. In certain embodiments, the pharmaceutical composition comprises about 8% to about 15% w / w of an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

[0015]

[0018] In certain embodiments, the active ingredient is a poorly water-soluble drug, hi certain embodiments, the active ingredient is roflumilast. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description of the Invention

[0019] Before describing the present invention in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described herein, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which will be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0017]

[0020] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety unless otherwise specified. Where the same term is defined in a publication, patent, or patent application and this disclosure is incorporated herein by reference, the definition in this disclosure shall be the controlling definition. For publications, patents, and patent applications referenced to describe a particular type of compound, chemistry, etc., the section relating to such compound, chemistry, etc. is the section of the document incorporated herein by reference.

[0018]

[0021] It should be noted that, as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "an active ingredient" includes a single ingredient and two or more different ingredients, and "a sulfate" includes a single sulfate salt and two or more different sulfate salts.

[0019]

[0022] The term "about," when used in connection with a numerical value, is meant to encompass numerical values ​​within a range whose lower limit is 5% less than the stated numerical value and whose upper limit is 5% greater than the stated numerical value.

[0020]

[0023] The term "effective" refers to an amount of a compound, drug, substance, formulation, or composition that is sufficient to result in a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of functional impairment or disability due to disease affliction. The amount may be alone or in combination with other compounds, drugs, or substances, either as a single dose or according to a multiple-dose regimen. One of ordinary skill in the art will be able to determine such amounts based on factors such as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0021]

[0024] "Pharmaceutically acceptable" means generally safe for administration to humans or animals. Preferably, a pharmaceutically acceptable component is one that is approved by a federal or state regulatory agency or is listed in the U.S. Pharmacopeia, published by the United States Pharmaceutical Convention, Inc., Rockville, Md., or other generally recognized pharmacopoeias for use in animals, and more particularly, humans.

[0022]

[0025] A "pharmaceutical composition" according to the present invention may be in the form of a composition in which the various active ingredients and the diluents and / or carriers are mixed with one another, or may take the form of a combined preparation in which the active ingredients are present in partially or completely different forms. An example of such a combination or combined preparation is a kit of parts.

[0023]

[0026] As used herein, the term "subject" or "patient" most preferably refers to a human. The term "subject" or "patient" can include any mammal that may benefit from the compounds described herein.

[0024]

[0027] A "therapeutic amount" or "therapeutically effective amount" is an amount of a therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent depends on factors such as the nature of the agent, the route of administration, the size of the subject receiving the therapeutic agent, and the purpose of the administration. The effective amount in each individual case can be determined empirically by one of ordinary skill in the art using methods established in the art.

[0025]

[0028] The term "topical" with respect to administration of a drug or composition refers to the application of such a drug or composition to an epithelial surface outside the body, including the skin or cornea. In this application, local delivery to the mucosal surface of a body orifice, e.g., the mucous membranes lining the mouth, vagina, or rectum, is considered a topical application.

[0026]

[0029] As used herein, "treat," "treating," or "treatment" of a disease or disorder means achieving one or more of the following: (a) lessening the severity and / or duration of the disorder; (b) limiting or preventing the occurrence of symptoms characteristic of the disorder being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder being treated; (d) limiting or preventing the recurrence of the disorder in patients who previously had the disorder; and (e) limiting or preventing the recurrence of symptoms of the disorder in patients who previously exhibited symptoms of the disorder.

[0027]

[0030] The abbreviation "w / v" denotes the relative concentrations of components in a composition as "weight to volume."

[0031] The abbreviation "w / w" expresses the relative concentrations of components in a composition as "weight for weight" (i.e., percentages refer to percentages of total weight) rather than on a volume or other amount basis.

[0028]

[0032] The present invention relates to topical pharmaceutical compositions comprising diethylene glycol monoethyl ether (DEGEE), the structural formula of which is as follows:

[0029] [ka]

[0030]

[0033] The present inventors have made the surprising discovery that topical pharmaceutical compositions comprising diethylene glycol monoethyl ether (DEGEE) maintained at an acidic pH are fully preserved without the addition of traditional antimicrobial preservatives. In preferred embodiments, the pharmaceutical compositions are maintained at a pH of less than about 6.3, or alternatively, less than about 6.0. In preferred embodiments, the pharmaceutical compositions further comprise an emulsifier blend of cetearyl alcohol, dicetyl phosphate (also known as cetearyl phosphate), and ceteth-10 phosphate (also known as ceteareth-10 phosphate), manufactured by Croda under the tradename Crodafos™ CES or Crodafos™ CES PHARMA.

[0031]

[0034] The pharmaceutical composition disclosed herein comprises diethylene glycol monoethyl ether and water. Diethylene glycol monoethyl ether, also known as 2-(2-ethoxyethoxy)ethanol or DEGEE, is sold under several trade names, including Transcutol® (Gattefosse Corporation, Paramus, NJ), Carbitol™ (The Dow Chemical Company, Midland, MI), Dioxitol® (Shell Oil Company, Houston, TX), and Poly-Solv DM (Monument Chemical, Houston, TX).

[0032]

[0035] DEGEE is often added as a cosolvent to topical products to increase the solubility of drugs in the formulation. The addition of DEGEE to topical formulations has also been shown to improve the skin penetration of topically administered pharmaceutically active substances, i.e., increase Cmax. Previously, aqueous-based creams and gels containing DEGEE without ethanol or isopropyl alcohol required the addition of antimicrobial preservatives to protect these non-sterile dosage forms from microbial growth due to accidental introduction during or after the manufacturing process. Because all useful antimicrobial agents are toxic, the concentration of antimicrobial preservatives must be as low as possible while still passing standard antimicrobial efficacy tests over the shelf life of the topical product. The present inventors have made the surprising discovery that topical pharmaceutical compositions containing DEGEE maintained at a pH below 6 can be fully preserved without the addition of antimicrobial preservatives. Examples of conventional antimicrobial preservatives that need not be included in the disclosed formulations include benzyl alcohol, parabens (e.g., methylparaben, ethylparaben, propylparaben, and butylparaben), phenoxyethanol, propylene glycol, bronopol, benzylkonium chloride, or benzethonium chloride.

[0033]

[0036] The concentration of diethylene glycol monoethyl ether in the formulation is sufficient to dissolve the active pharmaceutical ingredient and provide antimicrobial properties. In certain embodiments, the pharmaceutical composition contains more than 25% w / w of diethylene glycol monoethyl ether, sufficient to provide antimicrobial properties. In certain embodiments, the amount of diethylene glycol monoethyl ether can range from about 20% w / w to about 40% w / w, about 20% w / w to about 35% w / w, about 25% w / w to about 35% w / w, about 20% w / w to about 30% w / w, or about 25% w / w to about 30% w / w. For example, the pharmaceutical composition may contain diethylene glycol monoethyl ether in any of the following w / w percentages: 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, etc.

[0034]

[0037] The pharmaceutical composition comprising diethylene glycol monoethyl ether has a pH of less than about 6.3. In certain embodiments, the pharmaceutical composition has a pH of less than about 6.3, less than about 6.2, less than about 6.1, less than about 6.0, less than about 5.9, less than about 5.8, less than about 5.7, less than about 5.6, less than about 5.5, less than about 5.4, less than about 5.3, less than about 5.2, less than about 5.1, or less than about 5.0, or maintains this value. In certain embodiments, the pharmaceutical compositions of SHR0302 have a pH of about 3.5 to about 6.3, about 3.5 to about 6.2, about 3.5 to about 6.0, about 3.5 to about 5.5, about 4.0 to about 6.3, about 4.0 to about 6.2, about 4.0 to about 6.0, about 4.0 to about 5.5, about 4.5 to about 6.3, about 4.5 to about 6.2, about 4.5 to about 6.0, about 4.5 to about 5.5, about 5.0 to about 6.3, about 5.0 to about 6.2, about 5.0 to about 6.0, or about 5.5 to about 6.0. In certain embodiments, the pharmaceutical composition is formulated to have a pH of 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, or 6.3.

[0035]

[0038] In certain embodiments, the pharmaceutical composition further comprises an emulsifier blend of cetearyl alcohol (CAS 67762 30 0), dicetyl phosphate (CAS 2197 63 9), and ceteth-10 phosphate (CAS 50643-20-4). The emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate is manufactured by Croda under the trade name Crodafos™ CES. Crodafos™ CES PHARMA is manufactured using the same starting materials and processes, but undergoes rigorous quality control and release testing, and uses the names cetearyl alcohol, cetearyl phosphate, and ceteareth-10 phosphate, in line with standard practice for naming pharmaceutical excipients. This commercially available emulsifier blend is a self-emulsifying wax, which is primarily composed of the waxy substance cetearyl alcohol (cetyl alcohol (C 16 H 34 O) and stearyl alcohol (C 18 H 38 O) in combination with 10-20% dicetyl phosphate (cetearyl phosphate) and 10-20% ceteth-10 phosphate (ceteareth-10 phosphate). Self-emulsifying waxes form emulsions when blended with water. Crodafos™ CES spontaneously forms an emulsion with a pH of about 3 when added to water. A pH adjusting agent, such as sodium hydroxide solution, can be added to raise the pH to the desired value.

[0036] [ka]

[0037]

[0039] In certain embodiments, the amount of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate can range from about 5% to about 20% w / w, about 6% to about 20% w / w, about 8% to about 20% w / w, about 6% to about 15% w / w, or about 8% to about 15% w / w. For example, the pharmaceutical composition includes the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate in any of the following w / w percentages: 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.

[0038]

[0040] The pharmaceutical composition further comprises an active ingredient. The active ingredient may be present in a pharmaceutically effective amount, as known to those skilled in the art, depending on the particular active ingredient. Topical application of potent pharmacological agents to treat skin disorders has been found to provide superior delivery, reduced systemic exposure, and improved ease of use for patients. The molecular structure of the compound ultimately determines the drug's ability to penetrate the epithelium of the tissue to which the product is applied. For dermal applications, the selection of formulation components determines the maximum skin penetration the formulator can achieve.

[0039]

[0041] The formulations of the present invention can be used with a wide variety of active ingredients, and the active ingredient is not particularly limited. The active ingredient may be a water-soluble or poorly water-soluble drug. The topical formulations disclosed herein may be anorectal preparations, skin medications, oral and throat products, nasal preparations, ophthalmic preparations, ear preparations, sterile washes, and vaginal preparations. The formulations disclosed herein may be used with active ingredients such as analgesics, antibiotics, antiseptics, antifungals, antihistamines, anti-inflammatory agents, antipruritics, antipsoriatics, antivirals, antineoplastic agents, acne agents, cytostatics, local anesthetics, botanicals, retinoids, keratolytic agents, and corticosteroids.

[0040]

[0042] Diethylene glycol monoethyl ether can dissolve various poorly water-soluble drugs. Therefore, in certain embodiments, the active ingredient may be poorly water-soluble. Examples of poorly water-soluble active ingredients suitable for use in the present invention include, but are not limited to, ketoconazole, roflumilast, econazole nitrate, ivermectin, clobetasol propionate, calcipotriene, halobetasol propionate, tazarotene, oxymetazoline free base, and desonide. In certain embodiments, the API is roflumilast. In certain embodiments, the API is one of the aforementioned active ingredients other than roflumilast (i.e., the API is not roflumilast, but is one of the other specified active ingredients). An API with low water solubility is defined herein as an API with a water solubility of 60 mg / L or less. In certain embodiments, the active ingredient has a water solubility of 60 mg / L or less.

[0041]

[0043] Table 1, set forth below, provides water solubility data for exemplary active ingredients for use with the pharmaceutical compositions disclosed herein. In certain embodiments, the active ingredient is one or a combination of the active ingredients in Table 1.

[0042] [Table 1]

[0043]

[0045] Suitable pharmaceutical dosage forms include, but are not limited to, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, lotions, pastes, gels, or foams. In a preferred embodiment, the pharmaceutical composition may be formulated as an emulsion in the form of a cream or gel.

[0044]

[0046] For example, the pharmaceutical composition may be formulated in one of the following forms:

[0047] Oil-in-water emulsions: The pharmaceutical compositions may be emulsions comprising a discontinuous phase of hydrophobic components and a continuous aqueous phase comprising water and optionally one or more polar hydrophilic excipients, as well as solvents, cosolvents, salts, surfactants, emulsifiers, and other components. These emulsions may contain water-soluble or water-swellable polymers that help stabilize the emulsion.

[0045]

[0048] Water-in-oil emulsions: The pharmaceutical compositions may be emulsions that include a continuous phase of hydrophobic components and an aqueous phase that includes water and optionally one or more polar hydrophilic carriers, as well as 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.

[0046]

[0049] Microemulsions: The pharmaceutical compositions may be clear, thermodynamically stable, isotropic liquid systems containing oil, water, and surfactants, often combined with cosurfactants. Microemulsions may be water-continuous, oil-continuous, or bicontinuous mixtures. The pharmaceutical compositions may also optionally contain up to 60% water by weight. Higher levels may be appropriate in some compositions.

[0047]

[0050] Nanoemulsions: The pharmaceutical compositions can be isotropic dispersions containing water, oil, and emulsifiers. The systems can be oil-in-aqueous or aqueous-in-oil systems, forming nanometer-sized droplets or an oily phase. Nanoemulsions often have a higher loading capacity for lipophilic active ingredients than microemulsions. Hydrophobic and hydrophilic active ingredients can also be incorporated into nanoemulsions. Nanoemulsions can be formed by any suitable method known in the art, including high-pressure homogenization, microfluidization, and phase inversion.

[0048]

[0051] Thickened aqueous gels: The pharmaceutical compositions may include an aqueous phase thickened with a suitable natural, modified natural, or synthetic thickener, such as those described below. Alternatively, the thickened aqueous gel may be thickened using a suitable polyethoxylate alkyl chain surfactant, or other nonionic, cationic, or anionic system.

[0049]

[0052] Thickened hydroalcoholic gels: The pharmaceutical compositions may contain a blend of water and alcohol as the polar phase thickened with a suitable natural, modified natural, or synthetic polymer, such as those described below. Alternatively, the thickened hydroalcoholic gel may be thickened using a suitable polyethoxylate alkyl chain surfactant or other nonionic, cationic, or anionic system. The alcohol may be ethanol, isopropyl alcohol, or other pharmaceutically acceptable alcohol. In embodiments of the present invention, the amount of alcohol (e.g., ethanol) may be less than 20% to provide a self-preserving formulation.

[0050]

[0053] Hydrophilic gels: The pharmaceutical compositions can be systems in which the continuous phase contains at least one water-soluble or water-dispersible hydrophilic component other than water. The formulation can optionally also contain up to 60% by weight of water. Higher levels may be appropriate depending on the composition. Suitable hydrophilic components include one or more glycols, such as polyols, e.g., glycerin, propylene glycol, butylene glycol, polyethylene glycol (PEG), random or block copolymers of ethylene oxide, propylene oxide, and / or butylene oxide; polyalkoxylated surfactants with one or more hydrophobic moieties per molecule; silicone copolyols; blends of ceteareth-6 and stearyl alcohol; and combinations thereof.

[0051]

[0054] In addition to the active ingredient, diethylene glycol monoethyl ether, water, and an optional emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, the formulation may contain additional excipients typically present in such dosage forms, which vary depending on the type and desired characteristics of the dosage form.

[0052]

[0055] moisturizer

[0056] The compositions of the present invention may contain a humectant to enhance moisture retention. In emulsions, the humectant is often a component of the discontinuous or continuous hydrophobic phase. The humectant may be a hydrophilic material containing a humectant or a hydrophilic material containing an emollient. Suitable humectants include 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, theobroma cacao (cocoa) butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl octanoate, glyceryl hydroxybenzoate, glyceryl ... The following ingredients may be used: 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.

[0053]

[0057] surfactants and emulsifiers

[0058] Compositions according to the present invention can optionally include one or more surfactants to aid in emulsifying the composition and wetting the surface of the active ingredient or excipient. As used herein, the term "surfactant" refers to an amphiphile (a molecule having both covalently bonded polar and nonpolar regions) that can reduce the surface tension of water and / or the interfacial tension between water and an immiscible liquid. Surfactants include: Alkylaryl Sodium Sulfonate, Amerchol-CAB, Ammonium Lauryl Sulfate, Apricot Kernel Oil PEG-6 Ester, 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, Cholesterol-24, Cocamide Ether Sulfate, Cocamine Oxide, Cocobetaine, Cocodiethanolamide, Cocomonoethanolamine Coco-caprylate / caprate, dicetyl phosphate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, oleamide monoethanolamine disodium sulfosuccinate, docusate sodium, 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 Glyceryl Laurate, PEG-120 Methyl Glucose Dioleate, PEG-15 Cocamine, PEG-150 Distearate, PEG-2 Stearate, PEG-20 Methyl Glucose Sesquistearate, PEG-22 Methyl Ether, PEG-25 Propylene Glycol Stearate, PEG-4 Dilaurate, PEG-4 Laurate, PEG-45 / Dodecyl Glycol Copolymer, PEG-5 Oleate, PEG-50 Stearate, PEG-54 Hydrogenated Castor Oil, PEG-6 Isostearate, PEG-60 Hydrogenated Castor Oil, PEG-7 Methyl Ether, PEG-75 Lanolin, PEG-8 Laurate , PEG-8 Stearate, Pegoxol 7 Stearate, Pentaerythritol Cocoate, Poloxamer 124, Poloxamer 181, Poloxamer 182, Poloxamer 188, Poloxamer 237, Poloxamer 407, Polyglyceryl-3 Oleate, Polyoxyethylene Alcohol, Polyoxyethylene Fatty Acid Esters, Polyoxyl 20 Cetostearyl Ether, Polyoxyl 40 Hydrogenated Castor Oil, Polyoxyl 40 Stearate, Polyoxyl 6 and Polyoxyl 32, Polyoxylglyceryl Stearate, Polyoxyl Stearate, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80, PPG-26 Oleate, PROMULGEN™ 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 fatty acid glycerides, and emulsifying wax.

[0054]

[0059] Suitable phosphate ester surfactants include 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, PEG-7 dimethicone phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, and oleth-3 phosphate. phosphate, oleyl ethyl phosphate, oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4 phosphate, steartyl 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, triolyeyl phosphate, and tristearyl phosphate.

[0055]

[0060] Polymers and Thickeners

[0061] For certain applications, it may be preferable to formulate topical products thickened with soluble, swellable, or insoluble organic polymeric thickeners, such as natural and synthetic polymers or inorganic thickeners, including, but not limited to, acrylate copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, caroboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline wax, and methylcellulose.

[0056]

[0062] The formulation may include one or more thickening agents to impart viscosity so that the formulation may be provided in the form of a semi-solid, e.g., a lotion, gel, cream, or ointment. Examples of suitable thickening agents 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, acrylate copolymers, Carbomer 1382, Copolymer Type B, Carbomer Homopolymer Type A, Homopolymer Type B, Carbomer Homopolymer Type C, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, gum arabic, alginic acid, bentonite, carbomer, also known as carboxyvinyl polymers, such as those sold under the trademark Carbopol® (Lubrizol, Wickliffe, Ohio), carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate, methyl cellulose, poloxamer, polyvinyl alcohol, sodium alginate, tragacanth, and xanthan gum. The thickening agent may be present in the oil or lipophilic portion of the formulation. Examples of suitable lipophilic thickening agents include cetyl alcohol, stearyl alcohol, glyceryl stearate, white beeswax, microcrystalline wax, hydrogenated polyisobutane polymers, and emulsifying wax.

[0057]

[0063] Additional Components

[0064] Compositions according to the present invention may be formulated with additional components such as fillers, carriers and excipients commonly found in topical cosmetic and pharmaceutical products, including, but not limited to, foaming agents, propellants, antioxidants, sequestering agents, stabilizers, buffers, pH adjusters, skin penetration enhancers, chelating agents, film formers, dyes, pigments, fragrances, and other excipients to improve product stability or aesthetics.

[0058]

[0065] Antibacterial Efficacy Test (AET)

[0066] The pharmaceutical compositions disclosed herein can meet the European Pharmacopoeia's Criterion A for antimicrobial preservative effectiveness without the need for traditional preservatives. Testing for antimicrobial preservative effectiveness is described in the European Pharmacopoeia 7.0, Section 5.1.3, which is incorporated herein by reference. Microbial challenge organisms for the European Pharmacopoeia 7.0, Section 5.1.3 include P. aeruginosa (ATCC #9027), S. aureus (ATCC #6538), C. albicans (ATCC #10231), and A. brasiliensis (ATCC #16404). The European Pharmacopoeia's Criterion A for antimicrobial preservative effectiveness is described in Table 2 below.

[0059] [Table 2]

[0060]

[0068] The pharmaceutical compositions disclosed herein can meet the USP criteria for Category 2 (topical) products without the need for traditional preservatives. <51> and is incorporated herein by reference. Challenge organisms for USP antimicrobial effectiveness testing include P. aeruginosa (ATCC #9027), E. coli (ATCC #8739), S. aureus (ATCC #6538), C. albicans (ATCC #10231), and A. brasiliensis (ATCC #16404). USP criteria for Category 2 products are set forth in Table 3 below.

[0061] [Table 3]

[0062]

[0070] Administration and Dosage

[0071] In certain embodiments, the pharmaceutical composition is administered topically at regular intervals or other regimens. For example, the topical pharmaceutical composition can be administered once a day, twice a day, three times a day, once a week, twice a week, three times a week, or four times a week. The pharmaceutical composition can be administered for a predetermined period of time. For example, the topical pharmaceutical composition can be administered for a period of about two weeks to at least about six months, or until visual improvement of the skin condition or disease is observed. Exemplary durations of the treatment regimen include 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or 1 year. In a preferred embodiment, the topical pharmaceutical composition is administered twice or three times a day for a period of at least 3 months, 4 months, 5 months, or 6 months.

[0063]

[0072] Manufacturing method

[0073] Topical pharmaceutical compositions containing diethylene glycol monoethyl ether can be prepared by processes commonly used in the field of pharmaceutical formulations for topical application. To create a single-phase formulation, such as a liquid, the components of the formulation may be combined and mixed until a homogeneous solution or suspension of the active ingredient is obtained. To create a multi-phase formulation, such as an emulsion, for example, the components of the aqueous and oil phases may be combined separately and mixed until a homogeneous solution is obtained, and then the aqueous and oil solutions may be combined and mixed, such as by shear mixing, to form the formulation. The drug active(s) may be dissolved (molecularly dispersed), complexed, or associated with excipients or other actives, or may be particulate (amorphous or crystalline). The oil phase may be added to the aqueous phase, or the aqueous phase may be added to the oil phase. The phases may be combined and mixed at elevated temperatures, such as 50-90°C, room temperature, such as 20-30°C, or at temperatures between room temperature and elevated temperatures.

[0064]

[0074] The following examples illustrate, without limitation, certain specific embodiments of the present invention. [Example]

[0065]

[0075] While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0066]

[0076] Example 1

[0077] The following 25% diethylene glycol monoethyl ether (DEGEE) aqueous solutions were prepared according to the compositions listed in Table 4.

[0067] [Table 4]

[0068]

[0079] Four independent product samples of the composition in Table 4 were challenged with an inoculum of 1 x 10 per gram of microbial suspension. 5 ~1×10 6 The inoculation was performed to achieve an inoculum level of colony-forming units (CFU). The four challenge organisms tested were P. aeruginosa (ATCC #9027), S. aureus (ATCC #6538), C. albicans (ATCC #10231), and A. brasiliensis (ATCC #16404). The inoculated test samples were stored at 20-25°C for 28 days. The number of each challenge organism was determined by plate count method on days 0, 2, 7, 14, and 28. Plate counts were performed using TSBM (Modified Tryptic Soy Broth), TSA (Tryptic Soy agar), and SDA (Sabouraud Dextrose agar) as diluents to quantify the levels of microorganisms in each sample, at an initial dilution of 1:10 or 1:100 as determined by the plate count validation for this product.

[0069]

[0080] The European Pharmacopoeia's acceptance criteria for topical products are that bacteria must demonstrate a 2-log and 3-log log reduction, respectively, at days 2 and 7 relative to the initial zero inoculum level, and that no recovery of P. aeruginosa (ATCC #9027) or S. aureus (ATCC #6538) can occur at day 28. For the fungal species C. albicans (ATCC #10231) and A. brasiliensis (ATCC #16404), a 2-log reduction must occur at day 14, and no increase can occur at day 28 relative to the zero inoculum level. If these criteria (known as European Pharmacopoeia (EP) 5.1.3, Criterion A for Antimicrobial Preservative Effectiveness) are not met, the formulation "fails" the antimicrobial preservative test. These criteria are difficult to achieve with many preservative systems. The levels of preservatives added to achieve these results often have adverse effects on the product and / or are toxic. However, if the formulation and packaging combination passes EP Criteria A, the product is guaranteed to be in suitable storage conditions for sale in the United States, Canada, Europe, and Japan. As shown in Table 5, the 25% DEGEE aqueous blend passes all EP Criteria A tests when the pH is about 6.3 or less.

[0070] [Table 5]

[0071]

[0082] Example 2

[0083] The six pH-adjusted 25% diethylene glycol monoethyl ether (DEGEE) aqueous solutions listed in Table 5 of Example 1 (i.e., Compositions 2-7) were formulated according to the United States Pharmacopoeia (USP) <51> In addition, six pH-adjusted 20% DEGEE solutions and six pH-adjusted 10% DEGEE solutions were tested according to the USP Antimicrobial Effectiveness Test (AET) standard. <51> The antimicrobial efficacy test was conducted using the standard of the USP Antimicrobial Effectiveness Test. Table 6 shows the pH values ​​and USP AET results of these 18 DEGEE:water blends.

[0072] [Table 6]

[0073]

[0085] Four independent product samples of the composition in Table 6 were inoculated with a challenge microbial suspension at 1 x 10 per gram. 5 ~1×10 6 The five challenge organisms tested were P. aeruginosa (ATCC #9027), E. coli (ATCC #8739), S. aureus (ATCC #6538), C. albicans (ATCC #10231), and A. brasiliensis (ATCC #16404). The inoculated test samples were stored at 20-25°C for 28 days. The number of each challenge organism was determined by plate count on days 0, 2, 7, 14, and 28. Plate counts were performed at an initial dilution of 1:10 or 1:100, as determined by the plate count validation for this product, using Modified Tryptic Soy Broth (TSBM), Tryptic Soy agar (TSA), and Sabouraud Dextrose agar (SDA) as diluents to quantify the microbial levels in each sample.

[0074]

[0086] The acceptance criteria for topical products are that bacteria (i.e., P. aeruginosa (ATCC #9027), E. coli (ATCC #8739), S. aureus (ATCC #6538)) must show a 2-log reduction at day 14 relative to the zero inoculum level at the initial time. For the fungal species C. albicans (ATCC #10231) and A. brasiliensis (ATCC #16404), no increase can occur at day 14 or day 28 compared to the zero inoculum level. For bacteria, no increase can occur at day 28 compared to the zero inoculum level. These criteria (USP <51> If the USP AET (known as the Antimicrobial Effectiveness Test) is not met, the formulation "fails" the antimicrobial preservation test. Table 6 shows that for the 25% and 20% DEGEE aqueous solutions, all USP AET criteria were met across the entire pH range studied. For the 10% DEGEE aqueous solution, only the most acidic pH value (pH = 4.10) passed the USP AET. All DEGEE aqueous blends adjusted to pH values ​​above 5 failed the USP AET.

[0075]

[0087] Example 3

[0088] The following two 10% Crodafos™ CES (a commercially available self-emulsifying wax blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate) cream formulations were prepared to have the compositions shown in Table 7. For Cream Formulation 1, 25% diethylene glycol monoethyl ether (DEGEE) was added to the cream to act as a preservative for the cream.

[0076] [Table 7]

[0077]

[0090] Four independent product samples of the cream formulations shown in Table 7 were inoculated with a challenge microbial suspension at 1 x 10 per gram. 5 ~1×10 6The colony-forming unit (CFU) inoculum levels were achieved. The four challenge organisms tested were P. aeruginosa (ATCC #9027), S. aureus (ATCC #6538), C. albicans (ATCC #10231), and A. brasiliensis (ATCC #16404). The inoculated test samples were stored at 20-25°C for 28 days. The number of each challenge organism was determined by plate count method on days 0, 2, 7, 14, and 28. Plate counts were performed at an initial dilution of 1:10 or 1:100, as determined by the plate count validation for this product, using Modified Tryptic Soy Broth (TSBM), Tryptic Soy agar (TSA), and Sabouraud Dextrose agar (SDA) as diluents to quantify the microbial levels in each sample.

[0078]

[0091] To pass European Pharmacopoeia Criterion A, a cream formulation must have a 2-log reduction on day 2 and a 3-log reduction on day 7 for P. aeruginosa (ATCC #9027) and S. aureus (ATCC #6538) compared to an initial zero inoculum level, and no recovery of either organism from the cream after 28 days. For the fungal species C. albicans (ATCC #10231) and A. brasiliensis (ATCC #16404), a 2-log reduction must occur on day 14 and no increase can occur on day 28 compared to a zero inoculum level.

[0079]

[0092] As shown in Table 8, Cream Formulation 2 (10% Crodafos™ CES emulsion) reduced the initial inoculum level (1.3 x 10 per gram) of the challenge organism P. aeruginosa (ATCC #9027). 5Although the Emulsion Formulation 2 passed EU Criteria A in terms of CFU (log reduction), it failed to adequately inhibit microbial growth on days 2 (S. aureus), 7 (S. aureus, C. albicans, and A. brasiliensis), or 28 (A. brasiliensis) for S. aureus (ATCC #6538) and fungal challenge organisms C. albicans and A. brasiliensis. Therefore, Cream Formulation 2, which does not contain DEGEE, does not adequately protect against harmful effects that may result from microbial contamination or growth during storage and use of the formulation. However, with the addition of 25% DEGEE, Cream Formulation 1 exceeded the minimum inoculum log reduction values ​​for all challenge organisms at the time intervals specified in EU Criteria A.

[0080] [Table 8]

[0081]

[0094] Example 4

[0095] As noted in the background section, AET is considered a developmental test. While not routinely performed on individual products, products are expected to meet the requirements over their shelf life when tested. Cream formulations of roflumilast are disclosed in U.S. Patent No. 9,884,050. Certain roflumilast cream compositions were prepared as set forth in Table 9.

[0082] [Table 9]

[0083]

[0097] The cream formulations shown in Table 9 were stored for 0 days, 6 months at 25°C at 60% relative humidity (RH), and 6 months at 40°C at 75% RH. The cream formulations were then inoculated with a challenge microbial suspension at 1 x 10 per gram. 5 ~1×10 6The inoculation levels were determined to achieve colony-forming unit (CFU) inoculation levels. The four challenge organisms tested were P. aeruginosa (ATCC #9027), S. aureus (ATCC #6538), C. albicans (ATCC #10231), and A. brasiliensis (ATCC #16404). The inoculated test samples were stored at 20-25°C for 28 days. The number of each challenge organism was determined by plate count method on days 2, 7, and 28. Plate counts were performed at an initial dilution of 1:10 or 1:100, as determined by the plate count validation for this product, using Modified Tryptic Soy Broth (TSBM), Tryptic Soy agar (TSA), and Sabouraud Dextrose agar (SDA) as diluents to quantify the microbial levels in each sample.

[0084]

[0098] The results of the AET tests are set forth in Tables 10, 11, 12, and 13. Table 10 provides the AET results for the challenge organism P. aeruginosa (ATCC #9027). Table 11 provides the AET results for the challenge organism S. aureus (ATCC #6538). Table 12 provides the AET results for the challenge organism C. albicans (ATCC #10231). Table 13 provides the AET results for the challenge organism A. brasiliensis (ATCC #16404). As shown in Tables 10-13, the roflumilast cream formulation passed the European Pharmacopoeia Criterion A for antimicrobial preservative effectiveness at start-up (T=0) and after 6 months of storage at both long-term and accelerated stability conditions.

[0085] [Table 10]

[0086] [Table 11]

[0087] [Table 12]

[0088] [Table 13]

[0089] [000103] The foregoing description has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Those skilled in the art will recognize that variations and substitutions can be made to the description of the underlying invention.

Claims

1. 1. A topical pharmaceutical composition comprising: a pharma- ceutical effective amount of an active ingredient; Diethylene glycol monoethyl ether; and Contains water, The pH is 6.3 or less, Meets European Pharmacopoeia antimicrobial preservative effectiveness criterion A; A topical pharmaceutical composition that is free of antimicrobial preservatives.

2. 2. The topical pharmaceutical composition of claim 1, having a pH of 6.0 or less.

3. 2. The topical pharmaceutical composition of claim 1, having a pH of 5.0 to 6.

3.

4. 2. The topical pharmaceutical composition of claim 1, having a pH of 5.0 to 6.

0.

5. 10. The topical pharmaceutical composition of claim 1, which meets the United States Pharmacopoeia criteria for a Category 2 (topical) product.

6. 10. The topical pharmaceutical composition of claim 1 which is a cream.

7. 10. The topical pharmaceutical composition of claim 1, which is a gel.

8. 2. The topical pharmaceutical composition of claim 1, comprising about 25% to about 40% w / w diethylene glycol monoethyl ether.

9. 2. The topical pharmaceutical composition of claim 1, comprising about 25% to about 35% w / w diethylene glycol monoethyl ether.

10. 10. The topical pharmaceutical composition of claim 1, further comprising an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

11. 14. The topical pharmaceutical composition of claim 13, comprising about 8% to about 15% w / w of an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

12. 2. The topical pharmaceutical composition of claim 1, wherein the active ingredient has a water solubility of 60 mg / l or less.

13. 1. A topical pharmaceutical composition comprising: a pharma- ceutical effective amount of an active ingredient; Diethylene glycol monoethyl ether; An emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate; and Contains water, A topical pharmaceutical composition that meets the European Pharmacopoeia Criterion A for antimicrobial preservative effectiveness.

14. 14. The topical pharmaceutical composition of claim 13, which meets the United States Pharmacopoeia criteria for a Category 2 (topical) product.

15. 14. The topical pharmaceutical composition of claim 13, which is a cream.

16. 14. The topical pharmaceutical composition of claim 13, which is a gel.

17. 14. The topical pharmaceutical composition of claim 13, which is free of antimicrobial preservatives.

18. 14. The topical pharmaceutical composition of claim 13, having a pH of 6.3 or less.

19. 14. The topical pharmaceutical composition of claim 13, having a pH of about 5.0 to about 6.

3.

20. 14. The topical pharmaceutical composition of claim 13, comprising about 25% to about 40% w / w diethylene glycol monoethyl ether.

21. 21. The topical pharmaceutical composition of claim 20, comprising about 25% to about 35% w / w diethylene glycol monoethyl ether.

22. 14. The topical pharmaceutical composition of claim 13, comprising about 8% to about 15% w / w of an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

23. 14. The topical pharmaceutical composition of claim 13, wherein the active ingredient has a water solubility of 60 mg / l or less.

24. 1. A topical pharmaceutical composition comprising: Roflumilast; Diethylene glycol monoethyl ether; An emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate; and Contains water, The pH is 6.3 or less, A topical pharmaceutical composition that meets the European Pharmacopoeia Criterion A for antimicrobial preservative effectiveness.

25. 25. The topical pharmaceutical composition of claim 24, which meets the United States Pharmacopoeia criteria for a Category 2 (topical) product.

26. 25. The topical pharmaceutical composition of claim 24, which is paraben-free.

27. 25. The topical pharmaceutical composition of claim 24, which is free of propylene glycol.

28. 25. The topical pharmaceutical composition of claim 24, which is free of antimicrobial preservatives.

29. 25. The topical pharmaceutical composition of claim 24, having a pH of about 5.0 to about 6.

3.

30. 25. The topical pharmaceutical composition of claim 24, comprising about 25% to about 40% w / w diethylene glycol monoethyl ether.

31. 25. The topical pharmaceutical composition of claim 24, comprising about 8% to about 15% w / w of an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

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