Self-preservative topical pharmaceutical composition comprising diethylene glycol monoethyl ether

Abstract

A self-preserving topical pharmaceutical composition maintained at acidic pH comprising diethylene glycol monoethyl ether (DEGEE). The pH of the formulation may be maintained at a pH of less than 6.3, or alternatively less than 6.0. The topical pharmaceutical compositions disclosed herein are self-preservative and can meet the European Pharmacopoeia Antimicrobial Preservative Efficacy Standard A without the addition of traditional Antimicrobial Preservants. Certain pharmaceutical compositions further comprise an emulsifier blend of cetostearyl alcohol, a dicetyl phosphate, and a phosphate of ceteth-10, the emulsifier blend being produced from Croda with the trade name CrodafosTM CES.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 319,586, filed on March 14, 2022, and U.S. Provisional Application No. 63 / 370,143, filed on August 2, 2022, both of which are incorporated herein by reference. Technical Field

[0003] The subject matter disclosed herein relates generally to topical pharmaceutical compositions. As disclosed herein, the inventors of the present invention 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 conventional antimicrobial preservatives. In a preferred embodiment, the pharmaceutical composition is maintained at a pH of less than about 6.3, or 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, which is manufactured by Croda under the trade name Crodafos TM CES or Crodafos TM Produced by CES PHARMA. Background Art

[0004] Compared with other routes of administration, topical and transdermal delivery of drugs has multiple advantages.Topical and transdermal delivery can be used to continuously deliver drugs to the systemic circulation and avoid first-pass metabolism.By contrast, for oral drug delivery, there is a significant liver first-pass effect that may metabolize drugs prematurely.Topical and transdermal also have advantages over intravenous administration, which must be a sterile product and may be painful, thereby increasing the patient's non-compliance.On the other hand, topical and transdermal delivery can be non-sterile, non-invasive, and self-administered.

[0005] Most topical products are non-sterile dosage forms packaged in multi-dose containers. Antimicrobial efficacy testing first appeared in the 18th revision as a United States Pharmacopeia General Chapter, which became effective on September 1, 1970. The chapter is intended to guide 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 drug preparations rarely contain enough alcohol (ethanol or isopropanol) to produce preparations with antimicrobial activity sufficient to prevent the proliferation of microorganisms introduced into the product. For this reason, antimicrobial preservatives need to be added, especially to aqueous preparations, to prevent microbial proliferation after contamination during preparation, or to limit microbial contamination that may occur during normal storage and use conditions of multi-dose containers. If microbial proliferation is not limited by the topical preparation itself or by the addition of preservatives, then infection and deterioration of the preparation may occur, which may harm patients. 21C.FR§211.113(a)(2008) states that "appropriate written procedures should be established and followed to prevent harmful microorganisms in drug products that do not require sterilization."

[0006] Antimicrobial preservatives are defined as substances added to non-sterile dosage forms to protect them from microbial growth or the effects of microorganisms accidentally introduced during or after the preparation process. Benzyl alcohol, phenoxyethanol, methylparaben and propylparaben are examples of typical antimicrobial preservatives for topical products. Antimicrobial preservatives are not used as substitutes for good manufacturing practices, nor are they merely used to reduce the viable microbial population of non-sterile products. All available antimicrobial agents are toxic substances. In order to protect patients to the greatest extent, the concentration of preservatives should be lower than the level that may be toxic to humans. Since different multi-dose containers have different degrees of patient contamination risks, the concentration of preservatives may be related to specific packaging. For example, compared with packaging the same emulsion in a tube with a small orifice (whereby the emulsion is distributed), repeatedly "dipping" a finger into a wide-mouthed jar of emulsion causes the remaining emulsion in the jar to be contaminated by microorganisms. The risk is much greater.

[0007] For all multi-dose topical dosage forms, antimicrobial efficacy (whether inherent in the product or due to the addition of antimicrobial preservatives) must be established using written procedures. Additional expectations are that the preservative concentration required by the antimicrobial effectiveness test (Antimicrobial Effectiveness Testing, "AET") should be kept at a minimum, and AET should be performed on materials from the final product container. Additional general considerations for antimicrobial preservative testing include understanding that the efficacy of the antimicrobial preservative may be enhanced or weakened by the active ingredients of the product, or the preparations it is incorporated into, or the containers and closures used. Explore the microbial activity of the preparation in its final container during the shelf life to ensure that this activity will not be impaired by storage. Such exploration can be performed on samples removed from the final container immediately before the test. During the development of pharmaceutical preparations, it should be demonstrated that the antimicrobial activity of the preparation, as is or when necessary, with one or more suitable preservatives, provides sufficient protection from the adverse effects of microbial contamination or proliferation that may be produced during storage and use of the preparation. Therefore, AET is considered a development test and should not be routinely used to determine the quality of the finished product. Although not routinely performed on a specific product, if tested, the product is expected to meet the requirements during its shelf life. Summary of the invention

[0008] The present invention relates to topical pharmaceutical compositions comprising diethylene glycol monoethyl ether (DEGEE). The inventors of the present invention 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 conventional antimicrobial preservatives. In a preferred embodiment, the pharmaceutical composition is maintained at a pH of less than about 6.3, or 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, which emulsifier blend is manufactured by Croda under the trade name Crodafos TM CES or Crodafos TM Produced by CES PHARMA.

[0009] 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 less than or equal to 6.3, or alternatively less than or equal to 6.0. 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.

[0010] In certain embodiments, the pharmaceutical composition is an emulsion or a gel.

[0011] In certain embodiments, the pharmaceutical composition meets the European Pharmacopeia Efficacy of Antimicrobial Preservation Criteria A and / or the United States Pharmacopeia ("USP") Criteria for Category 2 (Topical) Products. Despite the fact that the preparation does not contain an antimicrobial preservative, the pharmaceutical composition can meet the European Pharmacopeia Antimicrobial Preservation Criteria A and / or the USP Class 2 Product Criteria. In certain embodiments, the pharmaceutical composition does not contain traditional antimicrobial preservatives such as benzyl alcohol, parabens (e.g., methylparaben, ethylparaben, propylparaben, and butylparaben), phenoxyethanol, propylene glycol, bropol, benzalkonium chloride, or benzethonium chloride.

[0012] 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.

[0013] In certain embodiments, the pharmaceutical composition further comprises an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate. In certain embodiments, the pharmaceutical composition comprises about 8% to about 15% w / w of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

[0014] In certain embodiments, the active ingredient is a poorly water-soluble drug. In certain embodiments, the active ingredient is roflumilast.

[0015] 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, an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, and water. In certain embodiments, the topical pharmaceutical composition has a pH of less than or equal to 6.3, or alternatively less than or equal to 6.0. 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.

[0016] In certain embodiments, the pharmaceutical composition is an emulsion or a gel.

[0017] In certain embodiments, the pharmaceutical composition meets the European Pharmacopoeia antimicrobial preservative efficacy standard A and / or USP Class 2 (topical) product standards. Despite the fact that the preparation does not contain an antimicrobial preservative, the pharmaceutical composition can meet the European Pharmacopoeia antimicrobial preservative efficacy standard A and / or USP Class 2 product standards. In certain embodiments, the pharmaceutical composition does not contain traditional antimicrobial preservatives, such as benzyl alcohol, parabens (e.g., methylparaben, ethylparaben, propylparaben, and butylparaben), phenoxyethanol, propylene glycol, Bropol, benzalkonium chloride, or benzethonium chloride.

[0018] In certain embodiments, the pharmaceutical composition comprises about 10% to about 40% w / w of diethylene glycol monoethyl ether. In certain embodiments, the pharmaceutical composition comprises about 20% to about 35% w / w of diethylene glycol monoethyl ether. In certain embodiments, the pharmaceutical composition comprises about 8% to about 15% w / w of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

[0019] In certain embodiments, the active ingredient is a poorly water-soluble drug. In certain embodiments, the active ingredient is roflumilast. DETAILED DESCRIPTION

[0020] Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methods, protocols and reagents described herein, as these may vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical terms and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs.

[0021] Unless otherwise noted, all publications, patents and patent applications cited herein are incorporated by reference in their entirety. In the case of a publication, patent, or patent application incorporated by reference herein and the same term defined in the present disclosure, the definition in the present disclosure represents the controlling definition. For publications, patents and patent applications cited to describe a particular type of compound, chemistry, etc., the portion related to such compound, chemistry, etc. is the document portion incorporated by reference herein.

[0022] Note that, as used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, "an active ingredient" includes a single ingredient as well as two or more different ingredients, and "a sulfate" includes a single sulfate as well as two or more different sulfates.

[0023] When used in conjunction with a numerical value, the term "about" is intended to encompass a range of values ​​having a lower limit that is 5% less than the indicated numerical value and an upper limit that is 5% greater than the indicated numerical value.

[0024] The term "effective" refers to an amount of a compound, agent, substance, preparation or composition that is sufficient to cause a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of damage or disability caused by disease affliction. This amount can be taken as a single dose or according to a multiple dose regimen, alone or in combination with other compounds, agents or substances. One of ordinary skill in the art will be able to determine such an amount based on factors such as the size of the individual, the severity of the individual's symptoms, and the particular composition or route of administration selected.

[0025] "Pharmaceutically acceptable" means generally safe for administration to humans or animals. Preferably, a pharmaceutically acceptable component is one that is approved by a regulatory agency of the federal or state government or listed in the US Pharmacopeia (published by the United States Pharmacopeial Convention, Inc., Rockville Md.), or other generally recognized pharmacopeia for use in animals, and more particularly for humans.

[0026] The "pharmaceutical composition" according to the present invention may be in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other, or may take the form of a combined preparation in which the active ingredients are present in part or in a completely different form. An example of such a combination or combined preparation is a kit-of-parts.

[0027] As used herein, the term "subject" or "patient" most preferably refers to a human. The term "subject" or "patient" may include any mammal that may benefit from the compounds described herein.

[0028] A "therapeutic amount" or "therapeutically effective amount" is an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent will vary depending on factors such as the nature of the agent, the route of administration, the size of the individual receiving the therapeutic agent, and the purpose of administration. The effective amount in each individual case can be determined empirically by a skilled artisan according to methods established in the art.

[0029] With respect to the administration of a drug or composition, the term "topical" refers to the application of such a drug or composition to an epithelial surface outside the body, including the skin or cornea. For such administration, topical delivery to the mucosal surface of a body opening (such as the oral cavity, vagina, or rectum) is considered to be a topical administration.

[0030] As used herein, "treat," "treating," or "treatment" of a disease or disorder means achieving one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the development of symptoms characteristic of the disorder or disorders being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder or disorders being treated; (d) limiting or preventing the recurrence of the disorder or disorders in a patient who previously had the disorder or disorders; and (e) limiting or preventing the recurrence of symptoms in a patient who previously had symptoms for the disorder or disorders.

[0031] The abbreviation "w / v" indicates the relative concentrations of components in a composition on a "weight to volume" basis.

[0032] The abbreviation "w / w" indicates the relative concentration of a component in a composition on a "weight to weight" basis (ie, percentages are percentages of the total weight) rather than on a volume or other amount basis.

[0033] The present invention relates to topical pharmaceutical compositions comprising diethylene glycol monoethyl ether (DEGEE). The structural formula of diethylene glycol monoethyl ether is provided below:

[0034]

[0035] The inventors of the present invention 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 conventional antimicrobial preservatives. In a preferred embodiment, the pharmaceutical composition is maintained at a pH of less than about 6.3, or alternatively less than about 6.0. In a preferred embodiment, the pharmaceutical composition further comprises an emulsifier blend of cetearyl alcohol, dicetyl phosphate (also known as cetearyl phosphate), and ceteth-10 phosphate (also known as ceteareth-10 phosphate), which is manufactured by Croda under the trade name Crodafos TM CES or Crodafos TM Produced by CES PHARMA.

[0036] The pharmaceutical compositions disclosed herein comprise diethylene glycol monoethyl ether and water. Diethylene glycol monoethyl ether is also known as 2-(2-ethoxyethoxy)ethanol, or DEGEE, and is sold under several trade names, including (Gattefosse Corporation, Paramus, NJ), Carbitol TM (The Dow Chemical Company, Midland, MI), (Shell Oil Company, Houston, TX), and Poly-Solv DM (Monument Chemical, Houston, TX).

[0037] DEGEE is often added to topical products as a cosolvent to increase the solubility of the drug in the formulation. It has also been shown that the addition of DEGEE to topical formulations enhances skin penetration, i.e., increases the C max . Traditionally, water-based emulsions and gels containing DEGEE but not containing ethanol or isopropanol need to add antimicrobial preservatives to protect these non-sterile dosage forms from the microbial growth of microorganisms introduced unintentionally during or after the preparation process. Because all available antimicrobial agents are toxic substances, the concentration of antimicrobial microbial preservatives should be as low as possible, while still passing the standard antimicrobial efficacy test during the shelf life of topical products. The inventor of the present application was surprised to find that the topical pharmaceutical composition containing DEGEE maintained at a pH less than 6 was fully preserved without adding antimicrobial preservatives. The example of the traditional antimicrobial preservative that does not need to be included in the disclosed preparation includes benzyl alcohol, parabens (for example, methylparaben, ethylparaben, propylparaben, and butylparaben), phenoxyethanol, propylene glycol, Bropol, benzalkonium chloride or benzethonium chloride.

[0038] 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 comprises greater than 25% w / w of diethylene glycol monoethyl ether, which is sufficient to provide antimicrobial properties. In certain embodiments, the amount of diethylene glycol monoethyl ether may be from about 20% w / w to about 40% w / w, from about 20% w / w to about 35% w / w, from about 25% w / w to about 35% w / w, from about 20% w / w to about 30% w / w, or from about 25% w / w to about 30% w / w. For example, the pharmaceutical composition comprises any of the following w / w % of diethylene glycol monoethyl ether: 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, etc.

[0039] The pharmaceutical composition comprising diethylene glycol monoethyl ether has a pH of less than about 6.3. In certain embodiments, the pharmaceutical composition has and maintains 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. In certain embodiments, the pharmaceutical composition of SHR0302 has 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.

[0040] 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 TM Produced by CES. Crodafos TM CES PHARMA is produced using the same starting materials and processes, but undergoes enhanced quality control and release testing and uses a nomenclature that conforms to standard conventions for naming pharmaceutical excipients: cetearyl alcohol, cetearyl phosphate, and ceteareth-10 phosphate. The commercially available emulsifier blend is a self-emulsifying wax, primarily a waxy substance: cetearyl alcohol (i.e., cetyl alcohol (C 16 H 34 O) and stearyl alcohol (C 18 H 38 O) in combination with 10-20% dicetyl phosphate (cetostearyl phosphate) and 10-20% ceteth-10 phosphate (cetostearyl phosphate). Self-emulsifying waxes form emulsions when blended with water. When Crodafos TMWhen CES is added to water, it spontaneously forms an emulsion with a pH of about 3. A pH adjusting agent, such as sodium hydroxide solution, may be added to increase the pH to the desired value.

[0041]

[0042] In certain embodiments, the amount of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate can range from about 5% w / w to about 20% w / w, about 6% w / w to about 20% w / w, about 8% w / w to about 20% w / w, about 6% w / w to about 15% w / w, or about 8% w / w to about 15% w / w. For example, the pharmaceutical composition comprises any of the following w / w % of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate: 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.

[0043] The pharmaceutical composition also comprises an active ingredient. Depending on the specific active ingredient, the active ingredient may be present in a pharmaceutically effective amount as known to those of ordinary skill in the art. It has been found that topical administration of potent agents for the treatment of dermatoses provides patients with superior delivery, lower systemic exposure, and higher ease of use. The molecular structure of the compound ultimately determines the ability of the drug to pass through the tissue epithelium to which the product is applied. For skin application, the selection of formulation components determines the maximum skin penetration that the formulator can achieve.

[0044] The preparations of the present invention can be used with a variety of active ingredients, and the active ingredient is not particularly limited. The active ingredient can be a water-soluble drug or a poorly water-soluble drug. The topical preparations disclosed herein can be anorectal preparations, skin preparations, oral and throat products, nasal preparations, eye preparations, ear preparations, sterile lavage solutions, and vaginal preparations. The preparations disclosed herein can be used with active ingredients, including, for example, analgesics, antibiotics, preservatives, antifungals, antihistamines, anti-inflammatory agents, antipruritics, antipsoriatic agents, antivirals, antitumor agents, acne agents, cytostatics, local anesthetics, botanicals, retinoids, keratolytics, and corticosteroids.

[0045] Diethylene glycol monoethyl ether can dissolve a variety of 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 the present invention include, but are not limited to, ketoconazole, roflumilast, econazole nitrate, ivermectin, clobetasol propionate, calcipotriol, 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 (that is, the API is not roflumilast, but one of the other active ingredients shown). APIs with low water solubility are defined herein as APIs 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.

[0046] Table 1 described below provides water solubility data for exemplary active ingredients used with the pharmaceutical compositions disclosed herein. In certain embodiments, the active ingredient is one of the active ingredients in Table 1 or a combination thereof.

[0047] Table 1. Exemplary active ingredients by water solubility

[0048] Active pharmaceutical ingredients Water solubility (mg / L) Ketoconazole 0.09 Roflumilast 0.54 Econazole nitrate 1.48* Ivermectin 4 Clobetasol Propionate 4 Calcipotriol 13.5 Halobetasol Propionate 14 Tazarotene 32 Oxymetazoline free base 52* Desonide 59 Azelaic acid 2,140 Minoxidil 2,200 Salicylic acid 2,480 Minocycline Hydrochloride 50,000 Oxymetazoline hydrochloride 145,000 Clindamycin phosphate 250,000 Urea 1,190,000

[0049] *ALOGPS calculated value

[0050] Suitable pharmaceutical dosage forms include, but are not limited to, emulsions, suspensions, sprays, oils, ointments, fatty ointments, emulsions, lotions, pastes, gels, or foams. In a preferred embodiment, the pharmaceutical composition can be formulated as an emulsion in the form of a cream or gel.

[0051] For example, the pharmaceutical composition can be formulated into one of the following forms:

[0052] Oil-in-water emulsions: The pharmaceutical composition may be an emulsion comprising a discrete phase of a hydrophobic component and a continuous aqueous phase comprising water and optionally one or more polar hydrophilic excipients and solvents, cosolvents, salts, surfactants, emulsifiers, and other components. These emulsions may include water-soluble or water-swellable polymers that help stabilize the emulsion.

[0053] Water-in-oil emulsions: The pharmaceutical composition may be an emulsion comprising a continuous phase of a hydrophobic component and an aqueous phase comprising water 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.

[0054] Microemulsions: The pharmaceutical composition may be a transparent, thermodynamically stable, isotropic liquid system containing oil, water, and a surfactant, often in combination with a co-surfactant. Microemulsions may be water-continuous, oil-continuous, or bi-continuous mixtures. The pharmaceutical composition may also optionally contain up to 60% by weight of water. In some compositions, higher levels may be appropriate.

[0055] Nanoemulsion: The pharmaceutical composition may be an isotropic dispersion system containing water, oil and an emulsifier. The system may be an oily system dispersed in an aqueous system, or an aqueous system dispersed in an oily system, thereby forming nano-sized droplets or an oil phase. Nanoemulsions generally have a higher loading capacity for lipophilic active ingredients than microemulsions. Hydrophobic and hydrophilic active ingredients may also be formulated in nanoemulsions. Nanoemulsions may be formed by any suitable method known in the art, including high pressure homogenization, microfluidization, and phase transition temperature.

[0056] Thickened aqueous gels: The pharmaceutical composition may comprise an aqueous phase thickened by a suitable natural thickener, modified natural thickener, or synthetic thickener as described below. Alternatively, the thickened aqueous gel may be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic, or anionic system.

[0057] Thickened hydroalcoholic gels: The pharmaceutical composition may comprise a blend of water and alcohol as the polar phase, which has been thickened by a suitable natural polymer, modified natural polymer, or synthetic polymer as described below. Alternatively, the thickened hydroalcoholic gel may be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic, or anionic system. The alcohol may be ethanol, isopropanol or other pharmaceutically acceptable alcohol. In embodiments of the invention, the amount of alcohol (e.g., ethanol) may be less than 20% and still provide a self-preserving formulation.

[0058] Hydrophilic gel: The pharmaceutical composition can be a system in which the continuous phase contains at least one water-soluble or water-dispersible hydrophilic component other than water. The formulation may also optionally contain up to 60% by weight of water. In some compositions, higher levels may be appropriate. Suitable hydrophilic components include one or more glycols such as polyols (e.g., glycerol, propylene glycol, butylene glycol, polyethylene glycol (PEG)), random or block copolymers of ethylene oxide, propylene oxide and / or butylene oxide, polyalkoxylated surfactants having one or more hydrophobic parts per molecule, silicone copolyols, blends of ceteareth-6 and stearyl alcohol, and combinations thereof, and the like.

[0059] In addition to the active ingredient, diethylene glycol monoethyl ether, water, and optionally an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, the formulation may contain additional excipients typically present in such dosage forms. Such excipients will vary depending on the type of dosage form and the desired characteristics.

[0060] Moisturizer

[0061] The compositions of the present invention may include a humectant to increase the hydration level. For emulsions, the humectant is typically a component of a discrete or continuous hydrophobic phase. The humectant may be a hydrophilic material including a wetting agent, or it may be a hydrophobic material 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 ester wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, behenyl alcohol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate Esters, 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 composition according to the invention may optionally comprise one or more surfactants to emulsify the composition and to aid in wetting the surface of the active ingredient or excipient. As used herein, the term "surfactant" means an amphiphile (molecule with covalently bound polar and non-polar regions) that is capable of reducing the surface tension of water and / or the interfacial tension between water and an immiscible liquid. Surfactants include, but are not limited to, sodium alkylaryl sulfonate, Amerchol-CAB, ammonium lauryl sulfate, almond oil PEG-6 esters, Arlacel, benzalkonium chloride, ceteareth-6, ceteareth-12, ceteareth-15, ceteareth-30, cetearyl alcohol / ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-10 phosphate, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide ether sulfate, cocamine oxide, coco-betaine, coco diethanolamide , Coconut oil monoethanolamide, coconut oil - caprylate / caprate, dicetyl phosphate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamidomonoethanolamine sulfosuccinate, sodium docusate, laureth-2, laureth-23, laureth-4, lauric acid diethanolamide, lecithin, methoxy PEG-16, methyl gluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2, oleth-20, PEG 6-32 Stearate, PEG-100 Stearate, PEG-12 Lauric Glyceryl, PEG-120 Methyl Glucose Dioleate, PEG-15 Cocoamine, PEG-150 Distearate, PEG-2 Stearate, PEG-20 Methyl Glucose Sesquistearate, PEG-22 Methyl Ether, PEG-25 Propylene Glycol Stearate, PEG-4 Dilaurate, PEG-4 Laurate, PEG-45 / Dodecyl Glycol Copolymer, PEG-5 Oleate, PEG-50 Stearate, PEG-54 Hydrogenated Castor Oil, P EG-6 Isostearate, PEG-60 Hydrogenated Castor Oil, PEG-7 Methyl Ether, PEG-75 Lanolin, PEG-8 Laurate, PEG-8 Stearate, Pegoxol 7 Stearate, Pentaerythrityl Cocoate, Poloxamer 124, Poloxamer 181, Poloxamer 182, Poloxamer 188, Poloxamer 237, Poloxamer 407, Polyglyceryl-3 Oleate, Polyoxyethylene Alcohol, Polyoxyethylene Fatty Acid Esters, Polyoxyl 20 Cetearyl Ether (cetostearylether), polyethylene glycol 40 hydrogenated castor oil, polyethylene glycol 40 stearate, polyethylene glycol 6 and polyethylene glycol 32, polyethylene glycol glyceryl stearate, polyethylene glycol 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 glyceryl, and emulsifying wax.

[0064] Suitable phosphate surfactants 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 phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth- 3 Phosphate, Oleyl Ethyl 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 Ethyl Phosphate, Dicetyl Phosphate, Dilaureth-10 Phosphate, Dimyristyl Phosphate, Dioleyl Phosphate, Tricetyl Phosphate, Triceteareth-4 Phosphate, Trilaureth-4 Phosphate, Trilauryl Phosphate, Trioleyl Phosphate, and Tristearyl Phosphate.

[0065] Polymers and Thickeners

[0066] For certain applications, it may be desirable to formulate topical products thickened with soluble, swellable, or insoluble organic polymer thickeners (such as natural and synthetic polymers) or inorganic thickeners, including but not limited to acrylate copolymers, carbomer 1382, carbomer type B copolymers, carbomer type A homopolymers, carbomer type B homopolymers, carbomer type C homopolymers, carboxyvinyl copolymers, carboxymethylcellulose, carboxypolymethylene, 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 may be provided in a semisolid form, such as a lotion, gel, emulsion, or ointment. Examples of suitable thickeners include, but are not limited to, soluble, swellable, or insoluble organic polymer thickeners, such as natural and synthetic polymers, or inorganic thickeners, including but not limited to acrylate copolymers, carbomer 1382, B-type copolymers, A-type carbomer homopolymers, B-type homopolymers, C-type carbomer homopolymers, carboxypolymethylene, carrageenan, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline wax, gum arabic, alginic acid, bentonite, carbomer (also known as carboxyvinyl polymers, such as those sold under the trade name (Lubrizol, Wickliffe, Ohio) sold), carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate, methyl cellulose, poloxamer, polyvinyl alcohol, sodium alginate, tragacanth gum, and xanthan gum. Thickeners 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 polyisobutane polymers, and emulsifying wax.

[0068] Additional components

[0069] The compositions according to the present invention can be formulated with additional components such as fillers, carriers and excipients that are conventionally present in cosmetic and pharmaceutical topical products. Additional components include, but are not limited to, foaming agents, propellants, antioxidants, sequestrants, stabilizers, buffers, pH adjustment solutions, skin penetration enhancers, chelating agents, film formers, dyes, pigments, fragrances and other excipients to improve the stability or aesthetics of the product.

[0070] Antimicrobial Effectiveness Test (AET)

[0071] Pharmaceutical compositions disclosed herein can meet European Pharmacopoeia antimicrobial preservation efficacy test standard A without traditional preservatives. Antimicrobial preservation efficacy test is described in European Pharmacopoeia 7.0 Section 5.1.3 (which is incorporated herein by reference). The challenge microorganisms of European Pharmacopoeia 7.0 Section 5.1.3 include Pseudomonas aeruginosa (P.aeruginosa) (ATCC#9027), Staphylococcus aureus (S.aureus) (ATCC#6538), Candida albicans (C.albicans) (ATCC#10231) and Aspergillus brasiliensis (A.brasiliensis) (ATCC#16404). European Pharmacopoeia antimicrobial preservation efficacy test standard A is described in Table 2 below.

[0072] Table 2. European Pharmacopoeia Preservative Effectiveness Test Standard A for Preparations for Dermal Application (NI = No Addition)

[0073]

[0074] The pharmaceutical compositions disclosed herein can meet USP Class 2 (topical) product standards without the need for traditional preservatives. Antimicrobial efficacy testing procedures are described in USP <51> (which is incorporated herein by reference) is described. The challenge microorganisms used for USP antimicrobial efficacy testing include Pseudomonas aeruginosa (ATCC#9027), Escherichia coli (E.coli) (ATCC#8739), Staphylococcus aureus (ATCC#6538), Candida albicans (ATCC#10231) and Aspergillus brasiliensis (ATCC#16404). USP Class 2 product standards are described in Table 3 below.

[0075] Table 3. USP Class 2 Antimicrobial Effectiveness Test Standards (NI = No Addition)

[0076]

[0077] Administration and Dosage

[0078] In certain embodiments, the pharmaceutical composition is topically administered with a regimen such as regular intervals. 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 within a specified time period. For example, the topical pharmaceutical composition can be administered for about two weeks to at least about six months, or until visually observed that the skin disorder or disease has improved. The exemplary time period of the treatment regimen includes two weeks, one month, six weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, or one 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.

[0079] Preparation method

[0080] The topical pharmaceutical composition containing diethylene glycol monoethyl ether can be prepared by processes typically used in the field of preparation of pharmaceutical preparations for topical application. In order to prepare a single-phase preparation such as a liquid, the ingredients of the preparation can be combined and mixed until a uniform solution or suspension of the active ingredient is obtained. For example, in order to prepare a multi-phase preparation 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 shear mixing, to form a preparation. One or more pharmaceutically active substances can be dissolved (molecular dispersion), complexed, or associated with excipients or other active substances, or can be particles (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 at an elevated temperature of 50-90°C or at a room temperature of 20-30°C, or at a temperature between room temperature and the elevated temperature.

[0081] The following examples illustrate certain embodiments of the invention without limitation.

[0082] Example

[0083] Although various embodiments have been described above, it should be understood that they are presented by way of example only and not by way of limitation. Therefore, the breadth and scope of the present disclosure should not be limited by any of the above exemplary embodiments. Unless otherwise specified herein or otherwise clearly contradictory to the context, the present disclosure encompasses any combination of all possible variations of the above elements.

[0084] Example 1

[0085] According to the composition listed in Table 4, the following 25% aqueous solution of diethylene glycol monoethyl ether (DEGEE) was prepared.

[0086] Table 4. Preservative efficacy of compositions of 25% DEGEE in water tested using European Pharmacopoeia Antimicrobial Preservative Effectiveness Standard A.

[0087] Ingredients (g) Composition 1 Composition 2 Composition 3 Composition 4 Composition 5 Composition 6 Composition 7 DEGEE 75.00 75.00 75.00 50.12 50.10 50.05 75.06 water 225.00 225.78 226.26 150.19 150.15 149.97 225.12 10%(w / v)HCl -- 0.01 0.01 -- -- -- 0.031 5% (w / v) HCl -- -- -- 0.0119 -- 0.0375 -- 2.5% (w / v) HCl -- -- -- 0.0163 0.0346 -- -- 1N NaOH -- 0.06 0.18 -- -- -- 0.115 2% NaOH -- -- -- -- -- 0.0580 -- 1% NaOH -- -- -- 0.0910 0.1123 0.0696 --

[0088] Four separate product samples of the composition in Table 4 were inoculated with a suspension of the challenge microorganism to achieve 1 × 10 5 Up to 1×10 6The inoculation level of colony forming units (CFU) was 1.477 mmol / l. The four challenge microorganisms tested were Pseudomonas aeruginosa (ATCC#9027), Staphylococcus aureus (ATCC#6538), Candida albicans (ATCC#10231) and Aspergillus brasiliensis (ATCC#16404). The inoculated test samples were stored at 20-25°C for 28 days. At 0, 2, 7, 14 and 28 days, the population of each challenge microorganism was determined by plate count. Plate counts were performed using Modified Tryptic Soy Broth (TSBM) as a diluent with an initial dilution of 1:10 or 1:100 to quantify the microbial levels in each sample and Tryptic Soy (TSA) and Sabouraud Dextrose (SDA) agar, as determined by the plate count validation of the product.

[0089] The European Pharmacopoeia stipulates that the acceptance criteria for topical products should have a count log reduction of 2 logs and 3 logs in the time period of the 2nd and 7th days, respectively, relative to the initial time zero inoculation level, and the recovery of Pseudomonas aeruginosa (ATCC#9027) or Staphylococcus aureus (ATCC#6538) cannot be obtained on the 28th day. For fungal species Candida albicans (ATCC#10231) and Aspergillus brasiliensis (ATCC#16404), a 2 log reduction must occur on the 14th day, and an increase cannot occur on the 28th day compared to the zero inoculation level. If these standards (called European Pharmacopoeia (EP) 5.1.3 antimicrobial preservation efficacy standard A) are not met, the preparation "fails" the antimicrobial preservation test. Many antiseptic systems are difficult to achieve these standards. Generally, the level of preservatives added to achieve these results has a harmful effect on the product and / or is at a toxic level. However, if the preparation and packaging combination pass EP standard A, it is believed that the product is fully preserved and can be sold in the United States, Canada, Europe and Japan. As seen in Table 5, the 25% DEGEE aqueous blend passed all EP Standard A tests when the pH was about or below 6.3.

[0090] Table 5. European Pharmacopoeia (EP) 5.1.3 Preservative Efficacy Standard A Test Results

[0091]

[0092] Example 2

[0093] According to the United States Pharmacopeia (USP <51> ) Antimicrobial Efficacy Test (AET) standard, 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 tested. In addition, the USP <51> Antimicrobial Efficacy Test Standard, six pH adjusted 20% DEGEE aqueous solutions and six pH adjusted 10% DEGEE aqueous solutions were tested. Table 6 shows the pH values ​​and USP AET results for the eighteen DEGEE:water blends.

[0094] Table 6. USP Antimicrobial Efficacy Test Results of 10% to 25% DEGEE Aqueous Solutions

[0095]

[0096] Four separate product samples of the composition in Table 6 were inoculated with a suspension of the challenge microorganism to achieve 1 × 10 5 Up to 1×10 6 The inoculation level of colony forming units (CFU) was 100. The five challenge microorganisms tested were Pseudomonas aeruginosa (ATCC#9027), Escherichia coli (ATCC#8739), Staphylococcus aureus (ATCC#6538), Candida albicans (ATCC#10231) and Aspergillus brasiliensis (ATCC#16404). The inoculated test samples were stored at 20-25°C for 28 days. At 0, 2, 7, 14 and 28 days, the population of each challenge microorganism was determined by plate count. Plate counts were performed using modified tryptic soy broth (TSBM) as a diluent with an initial dilution of 1:10 or 1:100 to quantify the microbial levels in each sample and tryptic soy (TSA) and Sabouraud dextrose (SDA) agar, as determined by the plate count validation of the product.

[0097] The acceptance criteria for topical products state that bacteria (i.e., Pseudomonas aeruginosa (ATCC #9027), Escherichia coli (ATCC #8739), Staphylococcus aureus (ATCC #6538)) should have a 2 log reduction in counts at day 14 relative to the initial time zero inoculation level. For the fungal species Candida albicans (ATCC #10231) and Aspergillus brasiliensis (ATCC #16404), no increase should occur at day 14 or day 28 relative to the zero inoculation level. For bacteria, no increase should occur at day 28 relative to the zero inoculation level. If these criteria are not met (called USP <51> Antimicrobial Efficacy Test), the formulation "failed" the antimicrobial preservation test. Table 6 shows that for the 25% DEGEE aqueous solution and the 20% DEGEE aqueous solution, all USP AET criteria were met over 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 aqueous blends of DEGEE adjusted to a pH equal to or greater than 5 failed the USP AET.

[0098] Example 3

[0099] The following two 10% Crodafos TM CES (a commercially available self-emulsifying wax blend of cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate) emulsion formulations. Emulsion formulation 1 had 25% diethylene glycol monoethyl ether (DEGEE) added to the emulsion to serve as a preservative for the emulsion.

[0100] Table 7. Two emulsion formulations whose preservative efficacy was tested using European Pharmacopoeia Antimicrobial Preservative Effectiveness Criteria A.

[0101] Ingredients (g) Emulsion preparation 1 Emulsion preparation 2 <![CDATA[Crodafos TM THESE]]> 30.04 30.04 water 190.08 266.82 1N NaOH 11.32 10.71 DEGEE 75.09 -- Final emulsion pH pH=5.58 pH=5.19

[0102] Four separate product samples of the emulsion formulations shown in Table 7 were inoculated with a suspension of the challenge microorganism to achieve 1 × 10 5 Up to 1×10 6The inoculation level of colony forming units (CFU) was 100. The four challenge microorganisms tested were Pseudomonas aeruginosa (ATCC#9027), Staphylococcus aureus (ATCC#6538), Candida albicans (ATCC#10231) and Aspergillus brasiliensis (ATCC#16404). The inoculated test samples were stored at 20-25°C for 28 days. On days 0, 2, 7, 14 and 28, the population of each challenge microorganism was determined by plate count. Plate counts were performed using modified tryptic soy broth (TSBM) as a diluent with an initial dilution of 1:10 or 1:100 to quantify the microbial levels in each sample as well as tryptic soy (TSA) and Sabouraud dextrose (SDA) agar, as determined by the plate count validation of the product.

[0103] To pass Ph. Eur. Standard A, the emulsion formulations needed to have a 2 log reduction at day 2 and a 3 log reduction at day 7 relative to the initial time zero inoculation level for P. aeruginosa (ATCC #9027) and S. aureus (ATCC #6538). Furthermore, after day 28, neither bacterium could recover from the emulsion. For the fungal species Candida albicans (ATCC #10231) and Aspergillus brasiliensis (ATCC #16404), a 2 log reduction must occur at day 14, and no increase may occur at day 28 relative to the zero inoculation level.

[0104] As can be seen in Table 8, for the initial inoculum level (1.3×10 5 CFU / g), emulsion formulation 2 (10% Crodafos TM CES emulsion) did pass EU Criteria A, but for Staphylococcus aureus (ATCC #6538) and the fungal challenge microorganisms Candida albicans and Aspergillus brasiliensis, the emulsion formulation failed to adequately inhibit microbial growth at Day 2 (S. aureus), Day 7 (S. aureus, Candida albicans, and Aspergillus brasiliensis), or Day 28 (Aspergillus brasiliensis). Therefore, Emulsion Formulation 2 without DEGEE did not provide adequate protection against adverse effects that could result from microbial contamination or proliferation during storage and use of the formulation. However, the addition of 25% DEGEE resulted in Emulsion Formulation 1 exceeding the minimum inoculum log reduction for all challenge microorganisms at the time intervals specified in EU Criteria A.

[0105] Table 8. Test results (log reduction) of two emulsion formulations and the test results of European Pharmacopoeia Preservative Effectiveness Standard A

[0106]

[0107] NI = no increase in CFU; I = increase in CFU, both compared to the inoculum level of the challenge microorganism.

[0108] Example 4

[0109] As described in the Background section, AET is considered a development test. Although it is not performed regularly on a particular product, if tested, the product is expected to meet the requirements during its shelf life. Emulsion formulations of Roflumilast are disclosed in U.S. Patent No. 9,884,050. Certain Roflumilast cream compositions described in Table 9 were prepared.

[0110] Table 9. Roflumilast cream formulation composition weights (to produce 2000 gram batches) whose preservative efficacy was tested using European Pharmacopoeia Antimicrobial Preservative Effectiveness Test Method A.

[0111] Element Emulsion preparation 3 Emulsion preparation 4 Emulsion preparation 5 Roflumilast 1.0088 g 3.0105 g 6.0057 g White Vaseline 200.57 g 200.76 g 200.38 g Isopropyl Palmitate 100.19 g 100.18 g 100.11 g <![CDATA[Crodafos TM THESE]]> 200.43 g 200.22 g 200.16 g Hexanediol 40.14 g 40.15 g 40.12 g Diethylene glycol monoethyl ether 500.40 g 500.51 g 500.27 g water <![CDATA[900.63 1 g]]> <![CDATA[897.02 2 g]]> <![CDATA[894.75 3 gram<!-- 14 --> ]]> 0.1N NaOH 73.73 g 74.29 g 74.51 g Final pH 5.21 5.18 5.35

[0112] 1 Due to evaporation losses during compounding, 23.12 gm of water was added back as a QS step

[0113] 2 Due to evaporation losses during compounding, 24.26 gm of water was added back as a QS step

[0114] 3 Due to evaporation losses during compounding, 24.02 gm of water was added back as a QS step

[0115] The emulsion formulations shown in Table 9 were stored at 25°C and 60% relative humidity (RH) for 0 days, 6 months, and 40°C and 75% RH for 6 months. The emulsion formulations were then inoculated with a challenge microbial suspension to achieve 1×10 5 Up to 1×10 6 The inoculation level of colony forming units (CFU) was 100. The four challenge microorganisms tested were Pseudomonas aeruginosa (ATCC#9027), Staphylococcus aureus (ATCC#6538), Candida albicans (ATCC#10231) and Aspergillus brasiliensis (ATCC#16404). The inoculated test samples were stored at 20-25°C for 28 days. On the 2nd, 7th and 28th days, the population of each challenge microorganism was determined by plate count. Plate counts were performed using modified tryptic soy broth (TSBM) as a diluent with an initial dilution of 1:10 or 1:100 to quantify the microbial levels in each sample and tryptic soy (TSA) and Sabouraud dextrose (SDA) agar, as determined by the plate count validation of the product.

[0116] The AET test results are described in Tables 10, 11, 12 and 13. Table 10 provides the AET results for the challenge microorganism Pseudomonas aeruginosa (ATCC#9027). Table 11 provides the AET results for the challenge microorganism Staphylococcus aureus (ATCC#6538). Table 12 provides the AET results for the challenge microorganism Candida albicans (ATCC#10231). Table 13 provides the AET results for the challenge microorganism Aspergillus brasiliensis (ATCC#16404). As shown in Tables 10-13, the Roflumilast emulsion formulations passed the European Pharmacopoeia Antimicrobial Preservative Effectiveness Standard A at the time of release (T=0) and after 6 months of storage under long-term and accelerated stability conditions.

[0117] Table 10. European Pharmacopoeia Antimicrobial Preservative Effectiveness Criterion A Results for Pseudomonas aeruginosa

[0118]

[0119] Table 11. European Pharmacopoeia Antimicrobial Preservative Effectiveness Criterion A Results for Staphylococcus aureus

[0120]

[0121]

[0122] Table 12. European Pharmacopoeia Antimicrobial Preservative Effectiveness Criterion A Results for Candida albicans

[0123]

[0124] Table 13. European Pharmacopoeia Antimicrobial Preservative Effectiveness Criterion A Results for Aspergillus brasiliensis

[0125]

[0126]

[0127] The foregoing description is provided for the purpose of illustration and description. The description is not intended to limit the invention to the precise form disclosed. Those skilled in the art will appreciate that modifications and substitutions may be made to the basic invention description.

Claims

1. A topical pharmaceutical composition comprising: A pharmaceutically effective amount of an active ingredient; Diethylene glycol monoethyl ether; and water, and wherein the topical pharmaceutical composition has a pH less than or equal to 6.3, wherein the pharmaceutical composition meets the European Pharmacopeia Efficacy of Antimicrobial Preservation Criteria A, and wherein the pharmaceutical composition does not contain an antimicrobial preservative.

2. The topical pharmaceutical composition of claim 1, wherein the topical pharmaceutical composition has a pH less than or equal to 6.

0.

3. The topical pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a pH of 5.0 to 6.

3.

4. The topical pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a pH of 5.0 to 6.

0.

5. The topical pharmaceutical composition of claim 1, wherein the pharmaceutical composition meets the United States Pharmacopeia Criteria for Category 2 (Topical) Products.

6. The topical pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a cream.

7. The topical pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a gel.

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

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

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

11. The topical pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises from about 8% to about 15% w / w of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

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

13. A topical pharmaceutical composition comprising: A pharmaceutically effective amount of an active ingredient; Diethylene glycol monoethyl ether; an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate; and water, and The pharmaceutical composition meets the European Pharmacopoeia antimicrobial preservative efficacy standard A.

14. The topical pharmaceutical composition according to claim 13, wherein the pharmaceutical composition meets the standards of United States Pharmacopeia Class 2 (topical) products.

15. The topical pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is a cream.

16. The topical pharmaceutical composition of claim 13, wherein the pharmaceutical composition is a gel.

17. The topical pharmaceutical composition of claim 13, wherein the pharmaceutical composition does not contain an antimicrobial preservative.

18. The topical pharmaceutical composition of claim 13, wherein the pharmaceutical composition has a pH less than or equal to 6.

3.

19. The topical pharmaceutical composition of claim 13, wherein the pharmaceutical composition has a pH of about 5.0 to about 6.

3.

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

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

22. The topical pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises from about 8% to about 15% w / w of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

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

24. A topical pharmaceutical composition comprising: Roflumilast; Diethylene glycol monoethyl ether; an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate; and water, wherein the topical pharmaceutical composition has a pH less than or equal to 6.3, and The pharmaceutical composition meets the European Pharmacopoeia antimicrobial preservative efficacy standard A.

25. The topical pharmaceutical composition of claim 24, wherein the pharmaceutical composition meets the standards of United States Pharmacopeia Class 2 (topical) products.

26. The topical pharmaceutical composition of claim 24, wherein the pharmaceutical composition does not contain parabens.

27. The topical pharmaceutical composition of claim 24, wherein the pharmaceutical composition does not comprise propylene glycol.

28. The topical pharmaceutical composition of claim 24, wherein the pharmaceutical composition does not contain an antimicrobial preservative.

29. The topical pharmaceutical composition of claim 24, wherein the pharmaceutical composition has a pH of about 5.0 to about 6.

3.

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

31. The topical pharmaceutical composition of claim 24, wherein the pharmaceutical composition comprises from about 8% to about 15% w / w of the emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

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