Topical naloxone compositions and methods for using the same

Abstract

To provide topical naloxone compositions for locally delivering naloxone to the skin of a subject.SOLUTION: A topical composition is a storage stable non-aqueous topical composition comprising naloxone free base and a non-aqueous vehicle, and is substantially free of naloxone N-oxide. The non-aqueous vehicle comprises two or more different polyethylene glycols having different average molecular weights. Also provided are methods of using the topical composition to locally deliver naloxone to a subject, as well as kits containing the topical naloxone compositions.SELECTED DRAWING: None

Description

[Background technology]

[0001] Naloxone is a narcotic μ-opioid receptor (MOR) antagonist with high affinity for μ-opioid receptors in the central nervous system. μ-opioid receptors are a class of opioid receptors that have affinity for enkephalins and β-endorphin, but low affinity for dynorphins. Three well-characterized variants of μ-opioid receptors are μ1, μ2, and μ3, which are typically found presynaptically (e.g., in the peritubular gray region and superficial dorsal horn of the spinal cord) or postsynaptically.

[0002] Activation of μ-opioid receptors (e.g., by agonists) can lead to analgesia, sedation, decreased blood pressure, itching, nausea, euphoria, decreased respiration, and meiosis. μ-opioid receptors can also be found in the intestinal tract, and activation of these receptors can sometimes inhibit peristaltic action, resulting in constipation. Naloxone, also commercially known as Narcan® or Evzio®, has lower affinity at κ- and δ-opioid receptors.

[0003] Naloxone is typically administered parenterally, such as by intravenous injection or infusion, which provides rapid delivery and complete bioavailability of the drug, making it predictable and controllable. Solution formulations for parenteral administration must be essentially free of particulate matter and sterile. They must be physically and chemically stable to ensure predictable efficacy and safety. Summary of the Invention

[0004] Aspects of the present invention include a topical naloxone composition for topically delivering naloxone to the skin of a subject. The topical composition, according to certain embodiments, is a storage-stable, non-aqueous topical composition comprising naloxone free base and a non-aqueous vehicle, and is substantially free of naloxone N-oxide. Methods for topically delivering naloxone to a subject using the topical composition are also provided, as well as kits containing the topical naloxone composition. [Brief explanation of the drawings]

[0005] [Figure 1] The observed percentage of naloxone N-oxide is shown for each of the various ointment formulations prepared from different PEG sources. [Figure 2] The observed percentage of naloxone N-oxide is shown for each of the various ointment formulations prepared from different PEG sources. [Figure 3] 1 shows the mean scratch bouts and cumulative scratch duration for mice on days 34 and 41 after application of topical compositions with 1) placebo (no naloxone active agent), 5, or 2) naloxone free base. [Figure 4] 1 shows the mean scratch bouts and cumulative scratch duration for mice on days 48 and 55 after application of topical compositions with 1) placebo (no naloxone active agent), 5, or 2) naloxone free base. [Figure 5] 1 shows the mean scratch bouts and cumulative scratch duration exhibited by mice on days 34 and 41 after application of 1) placebo (no naloxone active agent), or 2) topical composition with naloxone HCl. [Figure 6] 1 shows the mean scratch bouts and cumulative scratch duration exhibited by mice on days 48 and 55 after application of 1) placebo (no naloxone active agent), or 2) topical composition with naloxone HCl. [Figure 7A] 1 shows transepidermal water loss at 34 days for a placebo (no naloxone active agent) composition and a topical composition with naloxone free base. [Figure 7B] 1 shows transepidermal water loss at 48 days for a placebo (no naloxone active agent) composition and a topical composition with naloxone free base. [Figure 7C] 1 shows transepidermal water loss at day 55 for a placebo (no naloxone active agent) composition and a topical composition with naloxone free base. [Figure 8A] 1 shows transepidermal water loss at day 33 for a placebo (no naloxone active agent) composition and a topical composition with naloxone HCl. [Figure 8B] 1 shows transepidermal water loss at day 55 for a placebo (no naloxone active agent) composition and a topical composition with naloxone HCl. [Figure 9A] 1 shows exemplary photographs of mouse skin to which a placebo (no naloxone active agent) composition and a topical composition having naloxone free base and a hydrophobic delivery vehicle were applied. [Figure 9B] 1 shows exemplary photographs of mouse skin to which a placebo (no naloxone active agent) composition and a topical composition having naloxone free base and a hydrophobic delivery vehicle were applied. [Figure 10A] 1 shows exemplary photographs of mouse skin to which a placebo (no naloxone active agent) composition and a topical composition having only naloxone HCl and a polyethylene glycol containing hydrophilic delivery vehicle were applied. [Figure 10B] 1 shows exemplary photographs of mouse skin to which a placebo (no naloxone active agent) composition and a topical composition having only naloxone HCl and a polyethylene glycol containing hydrophilic delivery vehicle were applied. DETAILED DESCRIPTION OF THE INVENTION

[0006] Aspects of the present invention include topical naloxone compositions for topically delivering naloxone to the skin of a subject. The topical compositions, according to certain embodiments, are storage-stable, non-aqueous topical compositions comprising naloxone free base and a non-aqueous vehicle, and are substantially free of naloxone N-oxide. Methods for topically delivering naloxone to a subject using the topical compositions are also provided, as well as kits comprising the topical naloxone compositions.

[0007] Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, since the scope of the present invention will be limited only by the appended claims.

[0008] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range, and any other stated or intervening value within this stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0009] Certain ranges are presented herein with numerical values ​​preceded by the term "about." The term "about" is used herein to provide literal support for the exact number it precedes, as well as a number that is near or approximately the number it precedes. When determining whether a number is near or approximately a specifically recited number, the near or approximately unrecited number may be a number that, in the context in which it is presented, provides a substantial equivalent to the specifically recited number.

[0010] Unless otherwise defined, all technical and scientific terms used herein are defined by the The term has the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative exemplary methods and materials are described below.

[0011] All publications and patents cited herein are incorporated by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0012] It should be noted that, as used in this specification and the appended claims, the articles "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a predicate for use of exclusive terminology such as "solely" and "only" in connection with the recitation of claim elements, or for use of a "negative" limitation.

[0013] As will be apparent to those skilled in the art upon reading this disclosure, each of the separate embodiments described and illustrated herein has distinct components and features which may be readily separated from or combined with the features of any of the other various embodiments without departing from the scope or spirit of the invention. Any described method can be carried out in the order of events described or in any other order which is logically possible.

[0014] Although the apparatus and methods are described with functional descriptions for grammatical fluidity, it is expressly understood that unless expressly recited under 35 U.S.C. § 112, the claims should not necessarily be construed as limited by construction of "means" or "step" limitations, but should be accorded the full scope of meaning and equivalents of the definitions provided by the claims under the doctrine of legal equivalents, and that if the claims are expressly recited under 35 U.S.C. § 112, they should be accorded the full legal equivalents under 35 U.S.C. § 112.

[0015] In further describing various embodiments of the present invention, aspects of the topical compositions are first reviewed in more detail, followed by a detailed description of embodiments using the topical compositions to deliver naloxone to a subject to treat a skin condition, and then a review of kits including the subject topical naloxone compositions.

[0016] Topical Compositions As summarized above, aspects of the present invention include topical compositions for delivering an amount of naloxone free base to a subject. Thus, the topical compositions include naloxone free base. Naloxone free base is described by the following formula:

[0017] [ka]

[0018] In embodiments, the subject naloxone compositions are formulated to deliver naloxone free base to a subject locally. The term "topically" is used herein in its conventional sense to refer to a route of administration in which naloxone free base is delivered across the surface of the skin, e.g., subcutaneously, into the dermis, and into one or more of the epidermis, including the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale. Thus, topical compositions containing naloxone free base are formulated to be applied to any convenient location, such as the arms, legs, buttocks, abdomen, back, neck, scrotum, face, behind the ears, etc. In some embodiments, the skin is healthy, intact skin. In other embodiments, the skin may be skin in which one or more layers (e.g., the stratum corneum, stratum germinativum, stratum spinosum, stratum basale, etc.) are diseased, inflamed, or not completely intact. The phrase "not fully intact" is used herein in its conventional sense to mean that one or more layers of the not fully intact skin contain at least one perforation due to disease, inflammation, or other condition, where the not fully intact skin may, for example, include defective barrier properties (e.g., perforations) in one or more layers of the skin that cumulatively account for 0.01% or more, such as 0.05% or more, such as 0.1% or more, for example 0.5% or more, such as 1% or more, for example 2% or more, such as 3% or more, for example 5% or more, such as 10% or more, for example 25% or more, such as 50% or more, for example 75% or more, such as 90% or more, for example 95% or more, such as 97% or more (including 99% or more) of the surface area to which the topical naloxone composition is applied.

[0019] In certain embodiments, naloxone free base is delivered locally to the site of administration. The term "locally" is used herein in its conventional sense to mean that naloxone is delivered to within the vicinity of or below the site of application. In these embodiments, naloxone free base diffuses a predetermined distance from the site of application, for example, within 30 cm, for example, within 25 cm, for example, within 20 cm, for example, within 15 cm, for example, within 10 cm, for example, within 5 cm, for example, within 4 cm, for example, within 3 cm, for example, within 2 cm, for example, within 1 cm, for example, within 0.5 cm (including within 0.1 cm) of the point of application. In other words, in these embodiments, the compositions of the invention are administered locally with the intention of delivering naloxone to the site of administration or at a distance from the site of administration. The local penetration depth of the active free base into the skin at the application site can also vary depending on the components of the hydrophilic delivery vehicle (described below), and can be 0.01 mm to 15 mm, for example, 0.05 mm to 14.5 mm, for example, 0.1 mm to 14 mm, for example, 0.5 mm to 13.5 mm, for example, 1 mm to 13 mm, for example, 1.5 mm to 12.5 mm, for example, 2 mm to 12 mm, for example, 2.5 mm to 11.5 mm, for example, 3 mm to 11 mm, for example, 3.5 mm to 10.5 mm, for example, 4 mm to 10 mm (including a penetration depth into the skin at the application site of 5 mm to 10 mm). In some cases, such administration can also result in systemic administration of naloxone, such as systemic administration of low doses of naloxone.

[0020] In certain embodiments, the topical compositions of interest are formulated for extended delivery of naloxone to a subject. The term "extended delivery" as used herein refers to an extended period of time, such as over several hours (including 1 hour or more), for example, 2 hours or more, such as 3 hours or more, e.g., The term "over a period of time" is used to refer to a composition formulated to deliver naloxone over, for example, 4 hours or more, e.g., 5 hours or more, e.g., 6 hours or more, e.g., 7 hours or more. For the above ranges, the upper time period is, in some cases, 10 hours or less, e.g., 9 hours or less, e.g., 8 hours or less, e.g., 7 hours or less. In certain embodiments, the topical composition is formulated to deliver naloxone to a subject for a period ranging, for example, from 1 to 10 hours, e.g., from 2 hours to 9 hours, e.g., from 2 hours to 7 hours.

[0021] Depending on the application site and physiology of the subject, and the surface area of ​​the skin to which the subject naloxone compositions are applied, the amount of naloxone free base in a topical composition of interest can vary, and in some cases, the amount of naloxone ranges from 0.01 mg to 2000 mg, e.g., 0.02 mg to 1750 mg, e.g., 0.03 mg to 1500 mg, e.g., 0.04 mg to 1250 mg, e.g., 0.05 mg to 1000 mg, e.g., 0.06 mg to 750 mg, e.g., 0.07 mg to 500 mg, e.g., 0.08 mg to 250 mg, e.g., 0.09 mg to 100 mg, inclusive. In some embodiments, the amount of free base ranges from 1 mg to 200 mg, e.g., 2.5 mg to 175 mg, e.g., 5 mg to 150 mg, e.g., 7.5 mg to 125 mg, inclusive. In some embodiments, the amount of naloxone free base is from 0.01% w / w to 15% w / w, such as from 0.05% w / w to 12.5% ​​w / w, for example from 0.05% w / w to 10% w / w, including from 0.1% w / w to 10% w / w, for example from 0.1% w / w to 5% w / w, including from 0.5% w / w to 5% w / w, for example from 0.75% w / w to 2.5% w / w, of the total weight of the topical composition. In some embodiments, The amount of naloxone free base in the topical composition is 0.5% w / w, 0.75% w / w, 1% w / w, 1.5% w / w, 2% w / w, 2.5% w / w, 3% w / w, 3.5% w / w, 4% w / w, 4.5% w / w, 5% w / w, 5.5% w / w, 6% w / w, 6.5% w / w, 7% w / w, 7.5% w / w, 8% w / w, 8.5% w / w, 9% w / w, 9.5% w / w, or 10% w / w.

[0022] Additionally, the composition is substantially free of naloxone N-oxide, which has the following molecular formula: 19 H 21 NO5 and is described by the following structural formula:

[0023] [ka]

[0024] The composition is substantially free of naloxone N-oxide, such that the amount of naloxone N-oxide in the composition, if present, is 0.5 w / w or less, e.g., 0.2 w / w or less, including 0.1 w / w or less. In some examples, the composition does not contain detectable naloxone N-oxide, such that naloxone N-oxide cannot be detected in the formulation using the protocol described in the Experimental section below.

[0025] In some cases, the composition is shelf-stable. A shelf-stable composition of an embodiment of the invention retains naloxone after storage under storage conditions, e.g., packaged and sterile conditions at room temperature, for a period of time, e.g., 1 month or more, e.g., 3 months or more, including 6 months or more, e.g., 12 months or more. In some cases, the topical formulations are storage stable such that the composition and / or active agent properties, e.g., color, viscosity, active agent activity, etc., do not change substantially at room temperature and elevated temperatures, e.g., 40° C. or higher (including 50° C. or higher), over an extended period of time, e.g., 1 week or more, 2 weeks or more, 1 month or more, 6 months or more, 1 year or more.

[0026] The topical composition according to an embodiment of the present invention comprises a non-aqueous topical delivery vehicle. By "topical delivery vehicle" is meant a composition that carries naloxone free base and allows it to contact and pass through the skin of a subject. In an embodiment, the subject topical composition is non-aqueous. Because the topical delivery vehicle is non-aqueous, the vehicle does not contain water, for example, as a solvent. Thus, the vehicle (the composition comprising the vehicle and naloxone free base) does not contain water.

[0027] In some cases, the non-aqueous vehicle includes a polyethylene glycol component. The term "polyethylene glycol" is used herein in its conventional sense to refer to a polymeric compound having an ethylene oxide backbone structure, such as linear polyethylene glycol, branched polyethylene glycol, functionalized linear polyethylene glycol, or multi-functionalized branched polyethylene glycol, or any combination thereof.

[0028] Featured local delivery vehicle compositions include a polyethylene glycol component having an average molecular weight (e.g., a U.S. Pharmacopoeia designated molecular weight) of 100 g / mol to 7500 g / mol, e.g., 150 g / mol to 5000 g / mol, e.g., 200 g / mol to 2500 g / mol, e.g., 300 g / mol to 1500 g / mol. The term "average molecular weight" is used in its conventional sense to refer to the total weight of the polymer divided by the total number of molecules. In some embodiments, the polyethylene glycol component includes a polyethylene glycol having an average molecular weight of 200 g / mol to 2000 g / mol, e.g., 300 g / mol or 400 g / mol to 1500 g / mol. The average molecular weight of the polyethylene glycol can be determined by any suitable molecular weight determination protocol, including, but not limited to, titration, size exclusion chromatography, high-performance liquid chromatography, gel permeation chromatography, mass spectrometry, and the like, among others.

[0029] The polyethylene glycol component can comprise one or more different types of polyethylene glycol, e.g., two or more different types of polyethylene glycol, e.g., three or more different types of polyethylene glycol, e.g., four or more different types of polyethylene glycol, e.g., five or more different types of polyethylene glycol (including ten or more different types of polyethylene glycol). In certain embodiments, the polyethylene glycol component in a subject naloxone composition comprises a first polyethylene glycol and a second polyethylene glycol. In some such embodiments, the polyethylene glycol component may comprise a first polyethylene glycol (e.g., PEG 600 or less) that is liquid below room temperature (RT) and a second polyethylene glycol (e.g., PEG 1000 or greater) that is a waxy solid at or above RT. In some embodiments, the first polyethylene glycol component is a lower molecular weight polyethylene glycol having an average molecular weight of 1000 g / mol or less, and the second polyethylene glycol component is a higher molecular weight polyethylene glycol having an average molecular weight of 1000 g / mol or greater. For example, the first polyethylene glycol component may be a polyethylene glycol having an average molecular weight of 600 g / mol or less, such as 550 g / mol or less, for example 500 g / mol or less, for example 450 g / mol or less, for example 400 g / mol or less, for example 350 g / mol or less, for example 300 g / mol or less. For example, the first polyethylene glycol component is a polyethylene glycol having an average molecular weight in the range of 200 g / mol to 600 g / mol, for example 250 g / mol to 500 g / mol, for example 300 g / mol to 400 g / mol. In certain embodiments, the first polyethylene glycol component is a polyethylene glycol having an average molecular weight of 300 g / mol. In certain embodiments, the first polyethylene glycol component is a polyethylene glycol having an average molecular weight of 400 g / mol. The second polyethylene glycol component may be a polyethylene glycol having an average molecular weight of 1000 g / mol or more, such as 1050 g / mol or more, for example 1100 g / mol or more, for example 1150 g / mol or more, for example 1200 g / mol or more, for example 1250 g / mol or more, for example 1300 g / mol or more, for example 1350 g / mol or more, for example 1400 g / mol or more, for example 1450 g / mol or more (including polyethylene glycol having an average molecular weight of 1500 g / mol or more). For example, the second polyethylene glycol component may be a polyethylene glycol having an average molecular weight in the range of 1000 to 6000 g / mol, e.g., 1100 g / mol to 4000 g / mol, e.g., 1200 g / mol to 3000 g / mol, e.g., 1300 g / mol to 2000 g / mol (including 1400 g / mol to 1500 g / mol). In certain embodiments, the second polyethylene glycol component is a polyethylene glycol having an average molecular weight of 1450 g / mol. With respect to the total amount of polyethylene glycol present, the percentage that is polyethylene glycol of the first molecular weight, e.g., 300 or 500 g / mol, can vary from 20 to 90%, e.g., 30 to 70%, inclusive. The percentage that is polyethylene glycol of the second molecular weight, e.g., 1450 g / mol, can, in some cases, vary from 20 to 50%, e.g., 30 to 45%. When a first low molecular weight polyethylene glycol is combined with a second high molecular weight polyethylene glycol, the composition may contain more of the first polyethylene glycol than the second polyethylene glycol, for example, the amount of the first low molecular weight polyethylene glycol may exceed the amount of the second high molecular weight polyethylene glycol, for example by 2% or more, such as by 5% or more (including 10% or more).

[0030] In some cases, the storage-stable non-aqueous topical composition comprises 0.1-1 wt. % naloxone free base, 50-70 wt. % of a first polyethylene glycol having an average molecular weight of 300-400 g / mol, and 30-45 wt. % of a second polyethylene glycol having an average molecular weight of 1450 g / ml. Formulations of note include: 0.1% naloxone free base / 60~65% PEG400 / 39.9~34.9% PEG1450 0.5% naloxone free base / 60~65% PEG400 / 39.5~34.5% PEG1450 1% naloxone free base / 60~65% PEG400 / 39~34% PEG1450

[0031] In some embodiments, the polyethylene glycol is pharmaceutical-grade polyethylene glycol having a molecular weight certified (i.e., having a Certificate of Analysis) by a regulatory agency (e.g., the United States Pharmacopoeia, USP, National Formulary, European Pharmacopoeia, etc.). In some cases, at least the first polyethylene glycol component contains little or no peroxide at the time the composition is prepared, e.g., 50 ppm or less, e.g., 40 ppm or less (including 30 ppm or less, including 20 ppm or less, including 10 ppm or less, including 5 ppm or less, including 1 ppm or less). Commercially available polyethylene glycols that can be used in embodiments of the present invention include Super Refined™ polyethylene glycol (Croda, East Yorkshire, England), Emprove® Millipore polyethylene glycol (Merck KGaA, Darmstadt, Germany), Pluriol® polyethylene glycol (BASF), Japanese Pharmacopoeia Macrogol polyethylene glycol (NOF Corporation), etc.

[0032] Optionally, the non-aqueous delivery vehicle may contain one or more antioxidants. If present, the amount of one or more antioxidants may vary, in some cases ranging from 0.01 to 5.0% w / w, e.g., 0.02 to 2.0% w / w. Any convenient antioxidant that reduces the occurrence of impurities may be present, e.g., as described in the Experimental Section below; examples of such antioxidants include butylated hydroxytoluene (BHT), propyl gallate, and the like.

[0033] The amount of non-aqueous delivery vehicle (e.g., PEG) present in the topical naloxone composition may vary and may range from 90% w / w to 99.9% w / w, such as from 95% w / w to 99.9% w / w, for example from 99% w / w to 99.9% w / w.

[0034] Topical naloxone compositions can vary as desired. In some cases, the topical naloxone composition is an ointment. The term "ointment" is used to refer to a semi-solid preparation intended for external application to the skin or mucous membranes. In some cases, the ointment exhibits a loss on drying of 25% or less, e.g., 20% or less. In some cases, the ointment exhibits a viscosity in the range of 300,000 to 2,000,000 cp, e.g., 350,000 to 1,800,000 cp (including 400,000 to 1,700,000 cp). In some cases, the topical naloxone composition is a cream. The term "cream" is used to refer to a semi-solid dosage form containing one or more active pharmaceutical ingredients dissolved or dispersed in a suitable base. In some cases, creams exhibit viscosities in the range of 25,000 to 900,000 cp, e.g., 30,000 to 800,000 cp (including 50,000 to 700,000 cp). In some cases, the topical naloxone composition is a lotion. The term "lotion" refers to topical suspensions, solutions, and emulsions intended for application to the skin. In some cases, lotions exhibit a loss on drying of 40% or more, e.g., 50% or more. In some cases, lotions exhibit a viscosity in the range of 1,000 to 50,000 cp, e.g., 2,000 to 40,000 cp (including 5,000 to 30,000 cp). In some cases, the topical naloxone composition is a gel. The term "gel" refers to a semisolid system consisting of a suspension composed of small inorganic particles or large organic molecules interpenetrated by a liquid. In some cases, gels exhibit a loss on drying of 60% or more, e.g., 70% or more. In some cases, the gel exhibits a viscosity in the range of 5,000 to 100,000 cp, e.g., 5,000 to 70,000 cp. In certain cases, the topical naloxone composition can be formulated as a liquid and dispensed as a spray, aerosol, or foam.

[0035] Topical naloxone compositions according to embodiments of the invention are non-irritating to a subject's skin at the site of application. Skin irritation is referred to herein in a general sense to refer to adverse reactions to the skin, such as redness (erythema), pain, swelling (edema), or dryness, discoloration, or damage. Thus, the subject topical compositions are formulated such that, when applied to a subject's skin, the skin quality remains intact and the topical delivery of naloxone remains consistent throughout the dosing interval.

[0036] In some embodiments, the topical naloxone composition is formulated to deliver a predetermined amount of naloxone locally through one or more layers of the subject's skin.

[0037] In certain embodiments, a subject topical naloxone composition may be first applied to a patch and then applied to the subject's skin site, or a patch may be placed over the skin site to which the topical naloxone composition has been applied. The patch may be made from a material that does not absorb naloxone. Patches of interest include, but are not limited to, nonwoven fabrics, woven fabrics, films (including sheets), porous bodies, foams, paper, composite materials obtained by laminating a film onto a nonwoven or woven fabric, and combinations thereof. Nonwoven fabrics include polyethylene and polypropylene. The materials may include polyolefin resins such as polyethylene and polypropylene; polyester resins such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate; rayon, polyamide, poly(ester ether), polyurethane, polyacrylic resin, polyvinyl alcohol, styrene-isoprene-styrene copolymer, and styrene-ethylene-propylene-styrene copolymer, and combinations thereof. Fabrics may include cotton, rayon, polyacrylic resin, polyester resin, polyvinyl alcohol, and combinations thereof. Films may include polyolefin resins such as polyethylene and polypropylene; polyacrylic resins such as polymethyl methacrylate and polyethyl methacrylate; polyester resins such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate; and cellophane, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluororesin, styrene-isoprene-styrene copolymer, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymer, polyamide, and polysulfone, as well as combinations thereof. The paper may include impregnated paper, coated paper, fine paper, kraft paper, Japanese paper, glassine paper, synthetic paper, and combinations thereof. In some embodiments, the patch is an occlusive material.

[0038] The size of the patch can vary depending on the area on the skin to which the topical naloxone composition is applied; in some cases, the patch is sized to cover the entire application site on the subject. Thus, the patch can have a length ranging from 2 to 100 cm, e.g., 4 to 60 cm, and a width ranging from 2 to 100 cm, e.g., 4 to 60 cm. The surface area of ​​the patch of interest is 4 cm. 2 ~1000cm 2 , for example 5cm 2 ~500cm 2 , for example 10cm 2 ~250cm 2 , for example 15cm 2 ~100cm 2 (20cm 2~50cm 2 The range may be inclusive.

[0039] Methods for applying topical naloxone compositions Aspects of the present invention also include methods for applying the topical naloxone compositions of the present invention to a subject. As noted above, topical refers to a route of administration in which naloxone is delivered across the skin, e.g., to one or more of the subcutaneous tissue, the dermis, and the epidermis, including the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale. Thus, methods can include applying the subject naloxone compositions to skin sites such as the arms, legs, buttocks, shoulders, lower back, thighs, abdomen, back, neck, scrotum, face, and behind the ears. In some embodiments, methods include applying the compositions of the present invention to healthy, intact skin. In other embodiments, methods include applying the subject compositions to skin in which one or more layers (e.g., the stratum corneum, stratum germinativum, stratum spinosum, stratum basale, etc.) may be diseased, inflamed, or not completely intact, e.g., skin in which one or more layers, such as the stratum corneum, contain defective barrier properties (e.g., perforations) due to disease, inflammation, or other conditions. For example, the method may include applying a topical naloxone composition to a skin surface of a subject, wherein the skin comprises defective barrier properties (e.g., perforations) in one or more layers, cumulatively 0.01% or more, such as 0.05% or more, for example 0.1% or more, such as 0.5% or more, for example 1% or more, such as 2% or more, for example 3% or more, such as 5% or more, for example 10% or more, such as 25% or more, for example 50% or more, such as 75% or more, for example 90% or more, such as 95% or more, for example 97% or more (including 99% or more) of the surface area to which the topical naloxone composition is applied.

[0040] When describing the method of the present invention, the term "subject" refers to a person or organism to which the topical composition is applied and maintained in contact. Thus, the subject of the present invention can include, but is not limited to, mammals, such as humans and other primates, including chimpanzees and other ape and monkey species, dogs, rabbits, cats and other domesticated pets, and in certain embodiments, the subject is a human. The term subject is also meant to include a person or organism of any age, weight, or other physical characteristics, and the subject may be an adult, a child, or any other animal. The subject may be a child, infant, or newborn.

[0041] As described above, the methods of the present invention include applying a topical naloxone composition to a skin surface of a subject and maintaining the topical composition in contact with the subject for a period of time sufficient to deliver naloxone to the subject. In some embodiments, the methods include extended delivery of naloxone to the skin site of the subject. By "extended transdermal delivery" is meant that the topical composition is formulated to provide delivery of naloxone over an extended period of time, e.g., over several hours, including 1 hour or more, e.g., 2 hours or more, e.g., 3 hours or more, e.g., 4 hours or more, e.g., 5 hours or more (including 6 hours or more, e.g., 7 hours or more). For example, the topical composition can be formulated to deliver naloxone to the skin site of the subject for a duration of 0.1 hours to 20 hours, e.g., 0.5 hours to 15 hours, e.g., 1 hour to 10 hours, e.g., 2 hours to 7 hours.

[0042] In certain embodiments, the protocol can include multiple dosing intervals. "Multiple dosing intervals" means that two or more doses of topical composition are applied to the subject in sequence and maintained in contact with the subject.Thus, the first application of the topical composition is removed from contact with the subject (for example, washed off with water or wiped off with a damp cloth), and a second dose of the topical composition is applied to the skin surface of the subject.In practicing the method of the present invention, the treatment regimen can include two or more dosing intervals, for example, three or more dosing intervals, for example, four or more dosing intervals, for example, five or more dosing intervals (including ten or more dosing intervals).

[0043] The duration between dosing intervals in the treatment protocol of multiple dosing intervals can vary depending on the physiology of the subject or the treatment protocol determined by medical personnel.For example, the duration between dosing intervals in the treatment protocol of multiple dosing intervals can be predetermined or follow a regular interval.Therefore, the time between dosing intervals can vary, and can be 1 hour or more, for example 2 hours or more, for example 4 hours or more, for example 6 hours or more, for example 8 hours or more, for example 12 hours or more, for example 16 hours or more (including 24 hours or more).In certain embodiments, the protocol of multiple dosing intervals provides a time between dosing intervals of 1 day or more, for example 2 days or more, for example 3 days or more, for example 4 days or more, for example 5 days or more, for example 6 days or more, for example 7 days or more, for example 10 days or more (including 30 days or more).In some cases, the upper limit of the period between dosing intervals is within 30 days, for example 28 days or less, for example 21 days or less, for example 14 days or less, for example 7 days or less (including 3 days or less). In certain embodiments, the time between dosing intervals ranges, for example, from 2 to 30 days, for example, from 3 to 28 days, for example, from 4 to 21 days, for example, from 5 to 14 days, including from 6 to 10 days. In certain cases, the duration between dosing intervals may depend on the progress of treatment for a particular condition (as described in more detail below), skin sensitivity, skin dryness, or the extent to which the symptoms of the treated condition are alleviated (e.g., relief from itching).

[0044] According to certain embodiments, the method for applying and maintaining a topical naloxone composition in contact with a subject is used to treat or prevent a skin condition, such as an inflammatory skin disease, a non-inflammatory skin disease, pruritus, or one or more symptoms associated with an inflammatory skin disease, a non-inflammatory skin disease, or pruritus. For example, in some cases, the method includes applying a topical composition to the skin surface of a subject to treat or prevent an inflammatory skin disease, such as atopic dermatitis, eczema, psoriasis, or a combination thereof. In other cases, the method includes applying a topical composition to the skin surface of a subject to treat or prevent a non-inflammatory skin disease, such as chronic prurigo. In still other cases, the method includes locally treating or preventing pruritus by applying one or more of the above-mentioned topical naloxone compositions to the skin of a subject. In certain cases, the pruritus is pruritus associated with one or more of primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, neurological conditions, or pregnancy. In certain cases, the pruritus is pruritus associated with one or more of primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, neurological conditions, or pregnancy. In embodiments, the pruritus is drug-induced pruritus or pruritogen-induced pruritus. In certain embodiments, the pruritus is associated with a condition selected from shingles, psoriasis, hives, dysesthesias, Grover's disease, chronic kidney disease, and Hailey-Hailey disease. The pruritus may be accompanied by skin redness, bumps, patches or blisters, dry or cracked skin, leathery or scaly skin, and the method may also include applying a subject naloxone composition in an amount sufficient to treat one or more of the skin redness, bumps, patches or blisters, dry or cracked skin, leathery or scaly skin associated with the pruritus.

[0045] In certain embodiments, in methods of treating a skin condition, a topical naloxone composition can be applied directly to an affected area of ​​skin (e.g., an inflammatory skin condition, a non-inflammatory skin condition, or a site of pruritus). The topical composition can be applied to all or a portion of the affected area of ​​skin, for example, 5% or more, for example, 10% or more, for example, 25% or more, for example, 50% or more, for example, 75% or more, for example, 90% or more, for example, 95% or more (including 99% or more) of the affected area of ​​skin. In some cases, the topical composition is applied to the entire affected area of ​​skin. In certain cases, the topical composition is applied to an area larger than the affected area of ​​skin, for example, an amount of skin surface immediately adjacent to the affected skin area, for example, an additional 5% or more of the peripheral area on the skin (based on the size of the diseased skin), for example, an additional 10% or more, for example, an additional 15% or more (including an additional 25% or more of the peripheral area on the skin).

[0046] The term "treatment" is used herein in its conventional sense to mean that at least an improvement in symptoms associated with a condition suffered by a subject is achieved, where improvement is used in a broad sense to refer to at least a reduction in the parameters associated with the condition being treated, such as the magnitude of the symptoms. Thus, treatment also includes situations in which a pathological condition, or at least the symptoms associated therewith, are completely eliminated, such that the subject no longer suffers from the condition, or at least the symptoms that characterize the condition. The term "manage" is used herein in its conventional sense to mean that the symptoms associated with a condition suffered by a subject are at least controlled (i.e., the magnitude of the symptoms is maintained within a predetermined level), and in some cases, the symptoms are improved without eliminating the underlying condition.

[0047] The term "prevention" is used herein in its conventional sense to refer to the reduction or complete elimination of the occurrence of a particular condition, such as when a subject topical composition is prophylactically applied to a subject's skin surface and the indicated skin condition is completely prevented from occurring, or a reduction in the severity of the condition or symptoms associated with the condition is experienced by the subject. Accordingly, methods according to certain embodiments involve prophylactically applying a subject topical naloxone composition sufficient to reduce the severity of the condition or symptoms associated with the condition by 5% or more (e.g., based on the size of the affected skin, the amount of inflammation, etc.), e.g., 10% or more, e.g., 15% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g., 90% or more, e.g., 95% or more (including 99% or more), as determined by a qualified medical professional. In some embodiments, applying a topical naloxone composition according to a subject method is sufficient to completely eliminate the occurrence of any symptoms associated with the condition or skin disease. In some embodiments, prophylactically applying a topical naloxone composition to the skin surface of a subject is sufficient to reduce the duration of a skin condition, e.g., for 0.1 days or more, e.g., for 0.5 days or more, e.g., for 1 day or more, e.g., for 2 days or more, e.g., for 3 days or more, e.g., for 4 days or more, e.g., for 5 days or more, e.g., for 6 days or more, e.g., for 7 days or more (including 14 days or more). In other embodiments, prophylactically applying a topical naloxone composition to the skin surface of a subject is sufficient to reduce the severity of symptoms associated with a skin condition, such as itch. For example ..., for example, 1 time per hour or more, e.g., 2 times per hour or more, e.g., 3 times per hour or more, e.g., 5 times per hour or more, e.g., 10 times per hour or more, e.g., 15 times per hour or more, e.g., 25 times per hour or more, e.g., 3 times per hour or more, e.g., 4 times per hour or more, e.g., 5 times per hour or more, e.g., 6 times per hour or more, e.g., 7 times per hour or more, e.g., 8 times per hour or more, e.g., 9 times per hour or more, e.g., 10 times per hour or more, e.g., 15 times per hour or more, e.g., 14 times per hour or more, e.g. For example, 50 or more times per hour (including 100 or more times per hour) may be sufficient to reduce the number of times the skin surface is scratched depending on the skin condition. Where the method includes prophylactically treating pruritus, the topical naloxone composition may be applied to the subject's skin surface 1 hour or more, for example 3 hours or more, for example 6 hours or more, for example 12 hours or more (including 24 hours or more) before the onset of symptoms associated with pruritus (e.g., itching, skin redness, scaly skin, blisters or bumps, etc.).

[0048] In embodiments, the topical composition may be prophylactically applied to the skin surface of a subject 1 hour or more, such as 2 hours or more, for example 4 hours or more, such as 6 hours or more, for example 8 hours or more, such as 12 hours or more, for example 16 hours or more, such as 20 hours or more, for example 24 hours or more (including 48 hours or more) before the skin condition or its associated symptoms (e.g., pruritus induced by a drug or a pruritogen) are expected to occur.

[0049] In some embodiments, the method involves applying a topical naloxone composition to the skin surface of a subject to treat or prevent pruritus. The pruritus may be associated with one or more of primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, neurological conditions, and pregnancy, or may be drug-induced or pruritogen-induced pruritus. In certain embodiments, the naloxone composition is formulated to treat or prevent one or more of the following symptoms associated with pruritus: skin redness, skin bumps, spots, or blisters, dry or cracked skin, leathery or scaly skin. In these embodiments, applying the topical naloxone composition is sufficient to reduce the severity of the pruritus by, for example, 5% or more (e.g., based on a patient response survey, the number of times the skin surface is scratched during a given period of time), for example, 10% or more, for example, 15% or more, for example, 25% or more, for example, 50% or more, for example, 75% or more, for example, 90% or more, for example, 95% or more (including 99% or more). In certain cases, applying and maintaining the topical naloxone composition in contact with the skin surface is sufficient to relieve the pruritus. For example, applying a subject topical naloxone composition is sufficient to reduce the number of times the skin surface is scratched in response to the pruritus by 1 or more times per hour, for example, 2 or more times per hour, for example, 3 or more times per hour, for example, 5 or more times per hour, for example, 10 or more times per hour, for example, 15 or more times per hour, for example, 25 or more times per hour, for example, 50 or more times per hour (including 100 or more times per hour). Where the method includes prophylactically treating pruritus, the topical naloxone composition may be applied to the skin surface of the subject at least 1 hour before the onset of symptoms (e.g., itch) associated with pruritus, such as at least 3 hours before, for example at least 6 hours before, for example at least 12 hours before (including at least 24 hours before) the onset of the symptoms.

[0050] In other embodiments, the method includes applying a topical naloxone composition to a subject's skin surface in the treatment or prevention of an inflammatory skin condition, such as atopic dermatitis, eczema, or psoriasis. In certain embodiments, the skin condition is atopic dermatitis associated with pruritus. In some cases, the naloxone composition is formulated to treat or prevent symptoms associated with the inflammatory skin condition, such as itch caused by atopic dermatitis, eczema, or psoriasis. In these embodiments, applying the topical naloxone composition is sufficient to reduce the severity of symptoms (e.g., itch) associated with the inflammatory skin condition by, for example, 5% or more (e.g., based on a patient response survey, the number of times the skin surface is scratched during a given period), for example, 10% or more, for example, 15% or more, for example, 25% or more, for example, 50% or more, for example, 75% or more, for example, 90% or more, for example, 95% or more (including 99% or more). In certain cases, applying and maintaining a topical naloxone composition in contact with a skin surface is sufficient to relieve symptoms (e.g., itching) associated with an inflammatory skin condition. For example, applying a subject topical naloxone composition may be performed more than once per hour, e.g., more than twice per hour, e.g., more than three times per hour, e.g., more than five times per hour, For example, 10 or more times per hour, for example 15 or more times per hour, for example 25 or more times per hour, for example 50 or more times per hour (including 100 or more times per hour) is sufficient to reduce the number of times the skin surface is scratched in response to itching caused by the inflammatory skin condition.

[0051] In still other embodiments, the method comprises applying a topical naloxone composition to a subject's skin surface in the treatment or prevention of an inflammatory skin condition that has been found to be partially or completely resistant to treatment with other active agents, such as steroid therapy, anti-inflammatory agents, or immunosuppressants. In these embodiments, applying the topical naloxone composition described herein is sufficient to reduce the amount of steroid, anti-inflammatory, or immunosuppressant administered to the subject to treat the skin condition, e.g., by 5% by weight or more, e.g., 10% by weight or more, e.g., 25% by weight or more, e.g., 50% by weight or more, e.g., 75% by weight or more, e.g., 90% by weight or more (including 95% by weight or more). In certain embodiments, applying and maintaining a subject topical naloxone composition on the skin surface is sufficient to completely replace treatment of the inflammatory skin condition with a steroid, anti-inflammatory, or immunosuppressant.

[0052] In certain cases, the method includes applying a topical naloxone composition described herein to replace one or more doses of a steroidal therapeutic agent, an anti-inflammatory agent, or an immunosuppressant administered in the treatment of an inflammatory skin condition (e.g., atopic dermatitis, eczema, psoriasis), such as two or more, such as three or more, such as four or more, such as five or more, such as six or more, such as seven or more, such as eight or more, such as nine or more, such as ten or more, such as fifteen or more, such as twenty-five or more, such as fifty or more, such as seventy-five or more (including one hundred or more) scheduled administrations of a steroidal therapeutic agent, an anti-inflammatory agent, or an immunosuppressant for treating the inflammatory skin condition. Thus, applying and maintaining a topical naloxone composition as described herein may be sufficient to reduce the number of scheduled administrations of a steroid therapeutic agent, anti-inflammatory agent or immunosuppressant in the treatment of an inflammatory skin condition by 5% or more, such as 10% or more, for example 15% or more, such as 20% or more, for example 25% or more, such as 50% or more, for example 75% or more, such as 90% or more, for example 95% or more (including reducing the number of scheduled administrations of a steroid therapeutic agent, anti-inflammatory agent or immunosuppressant in the treatment of an inflammatory skin condition by 99% or more).

[0053] In certain embodiments, the subject methods are suitable for completely replacing the administration of steroidal therapeutic agents, anti-inflammatory agents, or immunosuppressants in the treatment of inflammatory skin conditions with the topical naloxone compositions described herein.

[0054] In certain embodiments, the method includes applying and maintaining one or more of the subject topical naloxone compositions in conjunction with the administration of steroid therapy, anti-inflammatory agents, or immunosuppressants in the treatment of inflammatory skin conditions. In some cases, when the topical naloxone composition is contacted with a subject, a reduced dose of steroid, anti-inflammatory agent, or immunosuppressant in the treatment of inflammatory skin conditions can be administered to the subject, for example, the dose of each scheduled administration of steroid, anti-inflammatory agent, or immunosuppressant is reduced by 5% or more, for example, 10% or more, for example, 15% or more, for example, 20% or more, for example, 25% or more, for example, 50% or more (including 75% or more). In some cases, one or more of the scheduled doses of administration of steroid, anti-inflammatory agent, or immunosuppressant are eliminated (i.e., skipped), for example, every scheduled dose, every two scheduled doses, every three scheduled doses, every four scheduled doses, or some other interval. In certain cases, applying one or more of the subject topical naloxone compositions may be administered in combination with consecutive scheduled doses of a steroid, anti-inflammatory, or immunosuppressant, e.g., two or more consecutive scheduled doses of a steroid, anti-inflammatory, or immunosuppressant, e.g., three or more consecutive scheduled doses (e.g., four or more consecutive scheduled doses). It is sufficient to eliminate the risk of steroid use (including scheduled medication).

[0055] In certain embodiments, the compositions of the present invention may be administered before, simultaneously with, or after another therapeutic agent for treating the same or unrelated condition. When provided simultaneously with another therapeutic agent, the subject topical naloxone compositions may be administered in the same or different compositions. Thus, the naloxone composition of interest and the other therapeutic agent may be administered to a subject in combination therapy. By "combination therapy" is intended administration to a subject such that the therapeutic benefits of the combination of substances are provided to the subject receiving therapy. For example, combination therapy may be achieved by administering a naloxone composition of the present invention together with a pharmaceutical composition having, in combination, a therapeutically effective dosage of at least one other agent, such as an anti-inflammatory agent, immunosuppressant, steroid, analgesic, anesthetic, antihypertensive, or chemotherapeutic agent, among other types of therapeutic agents, according to a specific dosing regimen. The separate pharmaceutical compositions may be administered simultaneously or at different times (i.e., on the same or different days, sequentially, in any order), so long as the therapeutic benefits of the combination of substances are provided to the subject receiving therapy.

[0056] When the naloxone composition is administered simultaneously with a second therapeutic agent to treat the same condition, the weight ratio of naloxone to the second therapeutic agent can be 1:2 to 1:2.5, 1:2.5 to 1:3, 1:3 to 1:3.5, 1:3.5 to 1:4, 1:4 to 1:4.5, 1:4.5 to 1:5, 1:5 to 1:10, and 1:10 to 1:25, or ranges thereof. For example, the weight ratio of naloxone to the second therapeutic agent can be in the range of 1:1 to 1:5, 1:5 to 1:10, 1:10 to 1:15, or 1:15 to 1:25. Alternatively, the weight ratio of the second therapeutic agent to naloxone is 2:1 to 2.5:1, 2.5:1 to 3:1, 3:1 to 3.5:1, 3.5:1 to 4:1, 4:1 to 4.5:1, 4.5:1 to 5:1, 5:1 to 10:1, and 10:1 to 25:1, or ranges thereof. For example, the weight ratio of the second therapeutic agent to naloxone can be in the range of 1:1 to 5:1, 5:1 to 10:1, 10:1 to 15:1, or 15:1 to 25:1.

[0057] As described above, aspects of the invention involve applying a topical naloxone composition to a subject for a period of time sufficient to deliver naloxone to the subject. In some embodiments, the method involves maintaining the topical composition in contact with the subject in a manner sufficient to deliver a target dosage of naloxone to the subject's local skin surface, e.g., a target dose determined by total local drug exposure or by average daily local drug exposure.

[0058] In some embodiments, the topical naloxone composition is formulated such that, when applied to the skin surface of a subject, the composition exhibits less transepidermal water loss than that exhibited by a naloxone composition containing a hydrophobic delivery vehicle, such as petrolatum. For example, the topical naloxone compositions described herein may be formulated such that, when applied to the skin surface of a subject, the composition exhibits less transepidermal water loss than that exhibited by a naloxone composition containing a hydrophobic delivery vehicle, such as petrolatum. 2 / hour or more, e.g., 1g / m 2 / hour or more, e.g. 1.5g / m 2 / hour or more, e.g., 2g / m 2 / hour or more, e.g. 3g / m 2 / hour or more, e.g. 5g / m 2 / hour or more, e.g. 10g / m 2 / hour or more (25g / m 2 / hour or more) than that exhibited by naloxone compositions containing a hydrophobic delivery vehicle. In some embodiments, the topical naloxone composition, when applied to the skin surface of a subject, is formulated to exhibit a transepidermal water loss of 25 g / m 2 / hour or less, e.g. 20g / m 2 / hour or less, e.g. 15g / m 2 / hour or less, e.g. 10g / m 2 / hour or less (5g / m 2 / hour).

[0059] In some embodiments, the method may include maintaining a topical naloxone composition in contact with the subject in a manner sufficient to deliver a predetermined amount of naloxone to the subject. When the protocol includes delivering a predetermined amount of naloxone to the subject, the topically delivered amount of naloxone may be between 0.001 mg and 2 mg, e.g., between 0.005 and 1.9 mg, e.g., between 0.01 mg and 1. The range may be in the range of 0.8 mg, for example, 0.05 to 1.7 mg, for example, 0.1 mg to 1.6 mg, for example, 0.5 mg to 1.5 mg (including 0.5 mg to 1 mg).

[0060] In certain embodiments, the predetermined amount of naloxone delivered to the subject can be a percentage of the total amount of naloxone present in the topical composition.For example, the predetermined amount of naloxone delivered locally to the subject can be 1% or more of the total amount of naloxone present in the topical composition, for example, 2% or more, for example, 5% or more, for example, 10% or more, for example, 25% or more (including 50% or more) of the total amount of naloxone present in the topical composition.In other words, the method can include maintaining the naloxone composition in contact with the subject in a manner sufficient to locally deliver 5% or more of the naloxone in the topical composition to the subject over a single dosage interval. For example, if the topical composition contains 1 mg of naloxone, the method may include maintaining the topical composition in contact with the subject in a manner sufficient to locally deliver 0.05 mg or more of the naloxone in the topical composition to the subject over a dosing interval, such as 0.1 mg or more, such as 0.25 mg or more, such as 0.4 mg or more, for example 0.45 mg or more (including 0.5 mg or more) of naloxone.

[0061] In certain embodiments, each of the subject methods described above may further comprise removing the topical composition from contact with the subject at the end of the dosing interval. For example, the topical composition may be removed from contact with the subject after maintaining the topical composition in contact with the subject for 0.1 hours or more, such as 0.5 hours or more, for example 1 hour or more, for example 2 hours or more, for example 4 hours or more, for example 6 hours or more, for example 8 hours or more, for example 12 hours or more, for example 16 hours or more, for example 20 hours or more (including 24 hours or more).

[0062] As described above, a dosing interval is a single administration in which the topical composition is applied and maintained in contact with the subject, which begins with applying the topical composition to the skin of the subject and ends when the topical composition is removed from contact with the subject or when all the naloxone in the composition is delivered locally to the subject. In certain embodiments, the protocol may include multiple dosing intervals. In practicing the method of the present invention, the treatment regimen may include two or more dosing intervals, for example, three or more dosing intervals, for example, four or more dosing intervals, for example, five or more dosing intervals (including ten or more dosing intervals).

[0063] In certain cases, subsequent dosing intervals in a treatment regimen may contain a higher or lower concentration of naloxone than the previous dosing interval.For example, the concentration of naloxone may be increased by 10% or more, for example, 20% or more, for example, 50% or more, for example, 75% or more, for example, 90% or more (including 100% or more) in subsequent dosing intervals.The upper limit of the increase in the concentration of naloxone in subsequent dosing intervals in some cases is 10 times or less, for example, 5 times or less, for example, 2 times or less, for example, 1 time or less, for example, 0.5 times or less (including 0.25 times or less).

[0064] Alternatively, the naloxone concentration may be decreased by, for example, 10% or more, for example 20% or more, for example 50% or more, for example 75% or more, for example 90% or more (including 100% or more) in a subsequent dosing interval. The upper limit for the decrease in naloxone concentration in a subsequent dosing interval is, in some cases, 10-fold or less, for example 5-fold or less, for example 2-fold or less, for example 1-fold or less, for example 0.5-fold or less (including 0.25-fold or less).

[0065] In other cases, a subsequent dosing interval may contain a different formulation of naloxone free base than the previous dosing interval, such as a different type of polyethylene glycol, amount of polyethylene glycol, etc., as described above.

[0066] In some embodiments, the skin is any area of ​​the skin to which the topical naloxone composition is applied. The skin is evaluated to assess changes, for example, to determine the quality or color of the skin at the application site and whether any damage, pain, swelling, or dryness is alleviated by maintaining the topical naloxone composition in contact with the subject. In certain embodiments, the skin is evaluated to assess transepidermal water loss by the skin.

[0067] The application site can be evaluated at any time during the subject method.In some cases, the skin is evaluated by observing or palpating the skin periodically, for example, every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours (including every 72 hours) or some other intervals, while the topical composition is kept in contact with the subject.For example, while the topical composition is kept in contact with the subject, the application site can be evaluated 15 minutes after applying the topical composition to the subject, 30 minutes after applying the topical composition, 1 hour after applying the topical composition, 2 hours after applying the topical composition, 4 hours after applying the topical composition, 8 hours after applying the topical composition, 12 hours after applying the topical composition (including 24 hours after applying the topical composition).

[0068] In other embodiments, the topical application site is evaluated after the topical composition is removed from contact with the subject. For example, the application site may be evaluated 30 minutes after removing the topical composition, e.g., 1 hour after removing the topical composition, e.g., 2 hours after removing the topical composition, e.g., 4 hours after removing the topical composition, e.g., 8 hours after removing the topical composition, e.g., 12 hours after removing the topical composition (including 24 hours after removing the topical composition).

[0069] In some embodiments, the site where the topical composition is applied is evaluated before the topical composition is applied to the subject, so as to record the color and texture of the skin before the start of the dosing interval.For example, the application site may be evaluated 5 minutes before applying the topical composition, for example 10 minutes before applying the topical composition, for example 30 minutes before, for example 60 minutes before, for example 120 minutes before, for example 240 minutes before (including 480 minutes before) applying the topical composition.If the method includes multiple dosing intervals that are applied consecutively, the application site may be evaluated after each removal of the topical composition from the skin and before the subsequent topical composition dose is applied.For example, if the first topical composition is removed, the application site may be evaluated 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, etc., after removal before the application of the second topical composition.Subsequent topical compositions may be applied to the previous application site immediately after the skin evaluation, or may be applied a predetermined time after the skin evaluation, for example 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after the skin evaluation.

[0070] In some cases, the method includes assessing the severity of the condition to be treated after administering the topical composition, for example, determining whether the composition is effective in treating the subject with the condition.Thus, the method can include assessing the severity of the subject's skin condition, such as inflammatory skin disease, non-inflammatory skin disease, pruritus, or one or more symptoms related to inflammatory skin disease, non-inflammatory skin disease, or pruritus, after administering the topical composition.For example, in some cases, the method includes assessing the severity of inflammatory skin disease, such as atopic dermatitis, eczema, psoriasis, or a combination thereof.In other cases, the method includes assessing the severity of non-inflammatory skin disease, such as chronic prurigo.In still other cases, the method includes assessing the severity of pruritus.In certain cases, the pruritus is pruritus associated with one or more of primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, neurological conditions, or pregnancy. In certain embodiments, the pruritus is drug-induced pruritus or pruritogen-induced pruritus. In certain embodiments, the pruritus is associated with a condition selected from shingles, psoriasis, hives, back paresthesia, Grover's disease, chronic kidney disease, and Hailey-Hailey disease. The pruritus can be characterized by skin redness, raised skin, patches or blisters, dry or cracked skin, or a reddened or swollen skin. The pruritus may be accompanied by skin redness, skin bumps, spots or blisters, dry or cracked skin, leathery or scaly skin, and the method may also include applying a subject naloxone composition in an amount sufficient to treat one or more of skin redness, skin bumps, spots or blisters, dry or cracked skin, leathery or scaly skin associated with the pruritus.

[0071] kit Kits for use in practicing certain methods described herein are also provided. In certain embodiments, the kit includes one or more topical naloxone compositions, such as those described above. In certain embodiments, the kit includes a dispensing device, such as a dropper or a metered dispenser. In some cases, the topical naloxone composition is present in a squeezable tube, such as a squeezable tube configured to hold an ointment. The kit may also include an applicator, such as a sponge, brush, doctor blade, spreading device, smoothing device, or a combination thereof. In certain embodiments, the kit further includes an overlay, such as a waterproof adhesive overlay, that can be used to cover the application site of the topical composition.

[0072] In a given kit that comprises two or more of the subject topical compositions, the compositions can be individually packaged or can be in a common container.In certain embodiments, the kit further comprises the instructions for practicing the subject method or the means for obtaining the instructions (for example, the website URL that directs the user to the web page that provides the instructions), and these instructions can be printed on a substrate, and the substrate can be one or more of package inserts, packaging, reagent containers, etc.In the subject kit, one or more components can be in the same or different containers, depending on what is convenient or desirable.

[0073] The following examples are offered by way of illustration and not by way of limitation.

[0074] experiment A. Detection of Decomposition Products The formulations detailed further below were prepared by first adding and stirring all ingredients except for PEG1450 (e.g., low MW PEG, NLX, and other additives such as antioxidants, glycerol, citric acid, etc.) at room temperature. The PEG1450 was then added and heated to approximately 50°C until all of the PEG1450 was dissolved. Once a homogeneous mixture was formed, it was filled into a tube (1-inch laminate tube with a 0.305-inch orifice from Albea) and sealed with foil. The inner layer of the laminate was linear low-density polyethylene (LLDPE). The filled tube was cooled to room temperature, forming an opaque ointment within the tube.

[0075] Stability testing of PEG-based naloxone ointment formulations was performed at 25°C, 40°C, and 60°C. The formation of one specific degradation product (also referred to as a "related substance") was consistently observed at each of these temperature conditions. This related substance typically appeared within one week of formulation preparation. Using primarily HPLC, we found that increasing temperature and humidity further increased the amount of degradation product relative to naloxone. This related substance was found to form at significantly higher levels and consistently across various excipients and storage conditions. Over time, a small percentage of naloxone appears to chemically degrade via an oxidative process, producing related substances (relative retention time (RRT) by HPLC of 0.79). The impurity at RRT 0.79 was an unknown related substance.

[0076] Naloxone HCl was also found to be unstable in PEG-based formulations. A 9.1% aqueous solution of naloxone HCl was prepared. 1.00 g of this 9.1% naloxone HCl was dissolved in 1.00 g of water. A PEG-based formulation was prepared at a total weight of 10.00 g of this 0.91% naloxone HCl by combining aqueous Cl with 4.70 g of PEG300 and 4.30 g of PEG1450. The stability of this naloxone HCl formulation at room temperature was assessed by HPLC over a two-month period. At month two, there was a significant increase in the growth of degradation products, as shown in Table 1 below, indicating that naloxone HCl is unstable even in this PEG-based formulation. Deg 1 is consistent with the relative retention time of the unknown related substance described above.

[0077] [Table 1]

[0078] B. Isolation and Identification of Naloxone N-Oxide The unknown related substances were isolated using a multi-step liquid chromatography method, which requires considerable time and effort due to the need to separate large amounts of PEG material to identify the degradation products of interest. Approximately 200 g of 1% naloxone free base ointment in PEG 300 was aged in a humidity chamber and used for isolation. The degradation products of interest were enriched in the formulation samples by C18 cartridges using 6.2 mM aqueous sodium 1-octanesulfonate, washed with 0.1% phosphoric acid, and then eluted with 40% methanol. Fractions containing the related substances were combined and lyophilized. The degradation products were analyzed using Shimadzu Prominence Isolation was performed by preparative HPLC using a Phenomenex Luna C18 column (5 μm, 21.2 × 150 mm) equipped with a Security Guard PREP C18 cartridge (21.2 × 15 mm).

[0079] A mobile phase of 35% methanol in 6.2 mM 1-octanesulfonic acid sodium salt in water with 0.1% phosphoric acid was used. The flow rate was 20 mL / min for an 18-minute isocratic run. The UV detector wavelength was 205 nm. Fractions were collected between 7 and 14 minutes, when a slope of 100 uV / sec and a level of 50,000 uV were observed. Reanalysis of the fractions by analytical HPLC indicated that the related substances present in the fraction samples were greater than 99% pure (Appendix A23). An Agilent Zorbax Eclipse XDB-C18 (5 μm, 4.6 x 150 mm) analytical column was used, running isocratically with 35% methanol in 6.2 mM water.

[0080] 1-Octanesulfonic acid sodium salt with a 0.1% phosphoric acid mobile phase over 15 minutes was used for analytical purity. Final isolation of impurities was accomplished by buffer removal using a strong cation exchange (SCX) cartridge washed with methanol and then eluted with 5% HCl in water. Fractions containing related substances were combined, and the pH was adjusted to 7.0 ± 0.5. The digest was extracted four times with equal volumes of a 3:1 solution of chloroform and isopropanol. The combined organic extracts were dried over sodium sulfate and concentrated to dryness. After purification on the SCX cartridge, the purity of the isolated digest was reduced to 92%.

[0081] Once sufficient milligram quantities of degradation products were isolated, they were characterized using mass spectrometry and NMR. High-resolution mass spectrometry data for the isolated degradation products was analyzed using a Waters UPLC Xevo system controlled by Waters UNIFI software. Acquisition was performed using a G2-XS QT. A Waters CORTECS UPLC Shield RP18 (1.6 μm 3 × 50 mm) column was used. Mobile phase A was 0.1% formic acid in water, and mobile phase B was 0.1% formic acid in acetonitrile. The flow rate was 0.2 mL / min. A gradient of 5% to 90% B over 5 min was applied. HRMS gave the molecular formula of C19H21NO5 with a mass error of less than 5 ppm.

[0082] NMR data were acquired on a Bruker 400 MHz spectrometer at ambient temperature, and chemical shifts are reported in ppm relative to TMS. 1 H, 13 C, and 15 NMR experiments using N nuclei, as well as two-dimensional NMR experiments, were performed. The observed signals in the acquired 1H NMR spectrum are consistent with the expected number and types of protons for the proposed structure. 13 Analysis of the C NMR spectrum showed 18 resonances of 19 carbons. Carbon assignments were made using available data from all NMR experiments. 15 The N NMR spectrum showed a single nitrogen resonance at 129.2 ppm. 15 The N shift supports the assignment of the proposed structure as an N-oxide. NMR data confirm that the naloxone core structure is intact, with no loss of proton or carbon signals. Importantly, 21 protons, 5 CH carbons, and 7 CH carbons were observed, indicating that the additional oxygen identified from the mass spectral data is not attached to any carbon atoms. Compared to naloxone, significant downfield shifts were observed for two exchangeable protons, as well as signals assigned to H9, H16, H17, and H10. Nitrogen NMR results showed a significant shift from 41.5 ppm (naloxone) to 129.2 ppm (degradant). These data indicated significant changes in the electrons surrounding the nitrogen atom due to the impurity. MS data confirmed that the impurity was naloxone N-oxide. Finally, the isolated related material was directly compared to a commercially available naloxone N-oxide standard by HPLC. The amount of naloxone N-oxide is first determined by a naloxone standard and then corrected for the response factor. The response factor for naloxone N-oxide is 1.19.

[0083] Comparison of naloxone and naloxone N-oxide structures:

[0084] [ka]

[0085] C. Naloxone forced degradation test 0.5% naloxone drug substance (Siegfried, Batch) was incubated for 18 hours or 2 weeks at 60°C in the presence of either 5N hydrochloric acid, 5N sodium hydroxide, or 3% hydrogen peroxide. The forced decomposition of 1530F001 was tested as a control. The sum of the related substances detected in the other treatments accounted for less than 1% of the peak area relative to the total area. In contrast, with 3% hydrogen peroxide, three degradation products were observed after 18 hours (1.75% at 0.66 RRT, 1.59% at 0.72 RRT, and 20.42% at 0.94 RRT). The peak at 0.72 corresponded to the related substance peak at 0.79 RRT, identified as naloxone N-oxide. The peak at 0.94 RRT coeluted with the naloxone peak. This forced degradation, compared with the other stresses, clearly demonstrates the reactivity of naloxone with peroxide and the potential for oxidative degradation.

[0086] D. Overview of Attempts to Stabilize PEG-Based Naloxone Ointment The main problem encountered during formulation development of PEG-based naloxone ointment is chemical instability due to interactions between naloxone and PEG upon oxidation. To address this stability issue, several different approaches have been investigated: Use of antioxidants (citric acid, BHT, tocopherol, and sodium metabisulfite) -Manufacturing, processing and storage management using inert gas (argon gas or nitrogen gas) Use of different PEGs (PEG300 vs. PEG400) Use of different PEG sources (PEG from Dow, Croda, BASF, EMD Millipore, and Clariant)

[0087] In summary, formulations with the best stability can be obtained by the following essential approaches: 1. Use Croda's super refined PEG 400 from an unopened container 2. Run argon protection during the mixing process 3. Blow argon into the melted ointment before filling. 4. Use an argon blanket in the headspace of the tube or container to prevent the ointment from coming into contact with air

[0088] 1. Antioxidant-based formulations The formulations were prepared by first adding all ingredients except PEG 1450 at room temperature and stirring. The PEG 1450 was then added and heated to approximately 50°C until all of the PEG 1450 was dissolved. Once a homogeneous mixture was formed, it was filled into a tube, capped, and cooled to room temperature to form an opaque ointment. Tocopherol and / or citric acid were added as antioxidants to the 1% PEG-based naloxone (NLX) ointment. Both PEG 300 and PEG 400 were tested for differences in stability over a 3-month period at 25°C. The results are shown in Table 2 below.

[0089] [Table 2-1]

[0090] [Table 2-2]

[0091] Although some differences were observed between formulations, neither the addition of antioxidants nor the change in PEG used stabilized the ointment to reduce naloxone N-oxide to sufficiently low (near-zero) levels. Additional testing of other formulations was performed at shorter time points. The results are shown in Table 3 below.

[0092] [Table 3]

[0093] Again, the addition of antioxidants did not sufficiently stabilize the naloxone in the ointment to near-zero levels of naloxone N-oxide.

[0094] 2. Use of low molecular weight PEG with very low peroxide value 1% (w / w) naloxone base ointments were prepared with PEG 300 or PEG 400 from different sources (Dow, Croda, BASF, EMD Millipore, and Clariant). PEGs from different sources were tested for the initial peroxide value of the low molecular weight PEGs used and for the stability of naloxone, as reflected by the growth of naloxone N-oxide degradants. These ointments were prepared using the following essential process: 1. Use PEG300 or PEG400 from an unopened container 2. Run argon protection during the mixing process 3. Blow argon into the melted ointment before filling. 4. Use an argon blanket in the headspace of the tube or container to prevent the ointment from coming into contact with air

[0095] The following 1% naloxone ointments were prepared, as summarized in Table 4 below:

[0096] [Table 4]

[0097] The percentage of naloxone N-oxide for each of these ointments is shown in Figures 1 and 2, and shows that ointments prepared from either PEG 300 or PEG 400 containing 12 ppm or less of peroxide exhibited negligible, pharmaceutically acceptable levels of naloxone N-oxide, while those prepared with lower molecular weight PEGs with higher levels of peroxide, even purified PEG 400 obtained from DOW, exhibited unacceptable growth of this identified degradant over time.

[0098] Table 5 below shows stability data for a 1% naltrexone base (w / w) formulation prepared with Croda super refined PEG 400 (1% API, 60% PEG 400, 39% PEG 1450). A response factor of 1.19 was used to calculate the level of the degradant naloxone N-oxide. For other unknown related substances, a response factor of 1 is assumed. These data in the table below indicate that for these assays, this formulation, prepared using a low-peroxide PEG 400 source and the method described above, has acceptable stability over two years at room temperature, based on 6-month, 40°C / 75% RH data.

[0099] [Table 5]

[0100] 3. Minimal effect of argon in processing and storage 1.0% naloxone free base (NLX) PEG-based ointment was applied to the Croda super ointment with and without argon sparging of the molten ointment and blanketing of the tube. Refined (low peroxide) PEG400 (60%) and PEG1450 (39%) formulations were also prepared. This same formulation was also prepared using non-low peroxide PEG400 and additional argon treatment. In accelerated stability studies at 40°C / 75% RH for 6 months, the low peroxide PEG400 (SR) formulations exhibited low concentrations of degradant 1 (naloxone N-oxide), while the higher peroxide PEG400 formulations exhibited higher concentrations of this degradant, with or without argon treatment (see Table 6 below). Note that for the higher peroxide PEG400 (Hi) formulations, this effect is actually partially obscured by further decomposition of nicotine N-oxide into other degradants at longer times. While the peroxide level of the PEG400 source has a significant effect, argon treatment does not result in any significant improvement in the decomposition rate.

[0101] [Table 6]

[0102] E. Identification of Additional Impurities 1. Gradient Assay Method The HPLC method used in the previous study (the "old" method) was suspected of containing another impurity that coeluted with the N-oxide. To provide quantification of this potentially new impurity, a "new" gradient method with a longer run time was developed. In addition, the "old" method had a sample concentration of 100 μg / mL, which resulted in a larger limit of quantitation (LOQ) and limit of detection (LOD). The "new" method provided greater sensitivity by increasing the sample concentration to 500 μg / mL. The "new" impurity method had an LOQ of approximately 0.03% and an LOD of 0.02%. The "old" impurity method was also utilized as a comparative assay method. The "new" method is used in the following examples.

[0103] [Table 7]

[0104] [Table 8]

[0105] 2. Effect of high molecular weight PEG A 1.0% naloxone free base (NLX) PEG-based ointment was prepared using Croda super refined (low peroxide) PEG400 (60%) and PEG1450 (39%) from two different manufacturers (Dow and BASF). Both ointments were prepared under argon. Table 9 shows that the growth of impurities at these five RRTs was consistently greater in DOW PEG1450, especially when stored at 40°C. In other words, the use of BASF PEG1450 was more stable than that of Croda PEG400.

[0106] [Table 9]

[0107] 3. Effect of antioxidants on formulations using BASF PEG1450 This same more stable formulation, BASF PEG1450 with Croda PEG400, was also prepared with the addition of selected antioxidants, BHT and galactopropyl, which are soluble in polyethylene glycol.

[0108] In this series of experiments, the following changes were made: First, storage at 60°C was replaced with storage at 40°C, which is a typical accelerated stability condition for this PEG ointment. This is because below 40°C, the composition may contain both liquid and solid components, while the ointment is liquid at 40°C, i.e., there is a phase transition to a liquid, which presents a more extreme challenge to stability than a simple temperature excursion even at 40°C. Storage at 60°C is similar to forced aging conditions and can be considered a worst-case scenario. Below 60°C, the ointment is entirely in liquid form. One month at 60°C is considered approximately two years at 25°C. This extreme temperature may allow for different degradation pathways, so some degradation that may occur at 60°C may not occur at lower temperatures. Second, in this study, the assay is reported as a % of the total ointment. The target API input is 1%.

[0109] Antioxidants have been used in the past in formulations using Dow PEG, but impurity concentrations were too high in the Dow PEG formulations, and no antioxidant benefit was observed. In Croda super-refined PEG 400 and BASF PEG 1450, overall impurity levels are much lower compared to previous formulations. In this case, the use of selected antioxidants in Croda PEG 400 and BASF PEG 1450 appears to be beneficial. Tables 10 and 11 compare formulations using Croda PEG 400 and BASF PEG 1450 with and without antioxidants, 1% propyl gallate, and 0.1% BHT. Lot 209-132-1 is similar to Lot 209-115-1 in Table 9, except that it contains BASF PEG 1450. Specifically, the formulation in Table 10 containing 0.1% BHT did not have any impurities greater than 0.2% after one month at 60°C, while the formulation containing 1% propyl gallate was also found to be more stable than the same formulation without the antioxidant.

[0110] [Table 10]

[0111] Storage conditions of 30°C were also used as a less severe accelerated condition without a phase transition to a liquid. Even after 3 months at 30°C, the formulation without antioxidants was less stable, the propyl gallate formulation was more stable, and the BHT formulation was the most stable.

[0112] [Table 11]

[0113] To determine the effect of BHT concentration on the stability of naloxone in this Kuroda PEG400 / BASF PEG1450, stability was tested at 40°C. BHT also showed improved stability.

[0114] [Table 12]

[0115] A third source with a molecular weight close to PEG1450, JP Macrogol 1500R, was also investigated (Table 6), demonstrating improved stability with antioxidants and compared favorably with Dow PEG1 It was found to be better than 450 but not as good as BASF PEG1450.

[0116] [Table 13]

[0117] Additional examples using antioxidants are shown in the table below, which confirm the aforementioned improvements with BHT and propyl gallate, as well as demonstrating that propyl gallate improved stability even at 0.1% propyl gallate. For this same Croda PEG400 / BASF PEG1450, data was collected comparing 0.05% propyl gallate with 0.1% BHT, with impurity levels of 0.05 and 0.06, respectively, at 60°C and an RRT of 0.81 after three months. Lower levels of 0.05% propyl gallate or 0.02% BHT, combined with the use of BASF PEG1450, improved the stability of the ointment.

[0118] [Table 14]

[0119] [Table 15]

[0120] F. Efficacy of naloxone ointment in a rat model of atopic dermatitis pruritus Atopic dermatitis skin symptoms were induced in mice (HOS:HR-1 hairless) by providing them with a special diet diet 10. All groups were treated daily with 0.1 ml / day of the ointment across the entire back of each mouse for three consecutive weeks, starting on day 34. Mice were videotaped for 30 minutes before administration (baseline activity) and observed for scratching over a one-hour period on days 34, 35, 38, 41, 45, 48, and 55 after application. After allowing the topical naloxone activator composition to dry for one hour, videotaping of scratching behavior was performed. Scratching behavior was monitored every five minutes for one hour, and the number of scratch bouts included one or more of the following behaviors: raising a hind leg, scratching the back, or lowering a leg to the floor. The cumulative duration of scratching behavior was also determined. Also measured was transepidermal water loss (TEWL) measured on days 34, 48, 55, and 20 (Phase 2), and days 33 and 55 (Phase 3). The treatment formulations by group are shown in Table 16 below.

[0121] [Table 16]

[0122] Figure 3 shows the mean scratch bouts and cumulative scratch duration exhibited by mice on days 34 and 41, and Figure 4 shows the mean scratch bouts and cumulative scratch duration exhibited by mice on days 48 and 55 to which topical compositions with 1) placebo (no naloxone active agent), 5, or 2) naloxone free base were applied. The results also compare the scratching behavior of mice to which topical compositions with a hydrophilic delivery vehicle containing polyethylene glycol or in the presence of a hydrophobic delivery vehicle (petrolatum).

[0123] Figure 5 shows the mean scratch bouts and cumulative scratch duration exhibited by mice on days 34 and 41, and Figure 6 shows the mean scratch bouts and cumulative scratch duration exhibited by mice on days 48 and 55 to which topical compositions with 1) placebo (no naloxone active agent) or 2) naloxone HCl were applied. The results also compare the scratching behavior of mice to which topical compositions with a hydrophilic delivery vehicle containing polyethylene glycol or in the presence of a hydrophobic delivery vehicle (petrolatum) were applied.

[0124] As shown in Figures 3-6, both the mean scratch bouts and cumulative scratch duration were reduced by topical delivery of either naloxone free base or naloxone HCl. In addition, the mean scratch bouts and cumulative scratch duration were significantly reduced by applying a topical composition having only naloxone active agent and a hydrophilic delivery vehicle (polyethylene glycol).

[0125] Figures 7A-7C show the transepidermal water loss for a placebo (no naloxone active agent) composition and a topical composition with naloxone free base on days 34, 48, and 55. As shown in Figures 7A-7C, compositions containing hydrophobic delivery vehicles exhibited greater transepidermal water loss, which is not typical as hydrophobic delivery vehicles such as petrolatum generally reduce water loss.

[0126] 8A-8B show the transepidermal water loss exhibited by a placebo (no naloxone active agent) composition and a topical composition having naloxone HCl on days 33 and 55. Similar to the composition having naloxone free base, the composition containing a hydrophobic delivery vehicle exhibited greater transepidermal water loss than that exhibited by a composition comprising only a polyethylene glycol containing hydrophilic delivery vehicle.

[0127] Figures 9A and 9B show exemplary photographs of the skin of mice to which a placebo (no naloxone active agent) composition and a topical composition having naloxone free base and a hydrophobic delivery vehicle were applied. Figures 10A and 10B show exemplary photographs of the skin of mice to which a placebo (no naloxone active agent) composition and a topical composition having only naloxone HCl and a polyethylene glycol containing hydrophilic delivery vehicle were applied. Comparing Figures 9A and 9B with Figures 10A and 10B demonstrates that the skin of mouse subjects to which a topical composition containing only a hydrophilic delivery vehicle was applied exhibited less irritation, redness, and damage resulting from scratching.

[0128] All tested naloxone topical compositions demonstrated anti-itch effects in the hairless mouse model. Compared to the placebo group, naloxone base + PEG (days 41 and 55) and naloxone base + Shea XP (days 48 and 55) significantly reduced scratching behavior. Compared to the placebo group, naloxone HCl + PEG (days 34 and 55) and naloxone HCl + Shea XP (days 34, 41, 48, and 55) significantly reduced scratching behavior. However, transepidermal water loss was significantly reduced with the PEG formulations containing either naloxone base or naloxone HCl. The Shea XP-containing formulation was significantly higher than the non-Shea XP-containing formulation.

[0129] In at least some of the above-described embodiments, one or more elements used in one embodiment may be used interchangeably in another embodiment unless such substitution is technically feasible. It will be understood by those skilled in the art that various other omissions, additions, and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and variations are intended to be within the scope of the subject matter defined by the appended claims.

[0130] It will be understood by those skilled in the art that the terms used herein in general, and in the appended claims in particular (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "including, but not limited to," etc.). It will be further understood by those skilled in the art that where a specific number of introduced claim recitations are intended, such intention will be expressly recited in the claim, and that in the absence of such recitation, no such intention exists. For example, as an aid to understanding, the following appended claims may include the use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, even if the same claim includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an," the use of such phrases should not be construed as meaning that introducing a claim statement with the indefinite article "a" or "an" limits any particular claim containing such an introduced claim statement to embodiments containing only one such statement (e.g., "a" and / or "an" should be construed to mean "at least one" or "one or more"). The same is true for the use of definite articles used to introduce claim statements. Also, even if a specific number of introduced claim statements is explicitly recited, those skilled in the art will recognize that such recitation should be construed to mean at least the recited number (e.g., a bare recitation of "two enumerations" without any other modifiers means at least two enumerations, or more than two enumerations).Furthermore, when a convention similar to "at least one of A, B, and C, etc." is used, such syntax is generally intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). When a convention similar to "at least one of A, B, or C, etc." is used, such syntax is generally intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Those skilled in the art will further appreciate that virtually any disjunctive word and / or disjunctive phrase presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B."

[0131] Furthermore, when features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member of the Markush group, or any subgroup of members of the Markush group.

[0132] As will be understood by those skilled in the art, for any and all purposes, including providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations thereof. Any listed range can be readily recognized as fully indicating and allowing for the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, upper third, etc. As will also be understood by those skilled in the art, all terms such as "up to," "at least," "greater than," "less than," etc., are inclusive of the recited numbers and refer to ranges that can subsequently be broken down into subranges as described above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items, etc.

[0133] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art that, in light of the teachings of this invention, certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

[0134] Thus, the foregoing merely illustrates the principles of the present invention. It will be appreciated that those skilled in the art will be able to devise various modifications, not explicitly described or shown herein, which embody the principles of the present invention and are within the spirit and scope of the present invention. Furthermore, all examples and conditional language recited herein are intended primarily to aid the reader in understanding the principles of the present invention and concepts provided by the inventors to further advance the art, and should not be construed as being limited to such specifically recited examples and conditions. Furthermore, all statements herein reciting principles, aspects, and embodiments of the present invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Furthermore, such equivalents are intended to include both currently known equivalents and future-developed equivalents, i.e., any elements developed to perform the same function, regardless of structure. Furthermore, nothing disclosed herein is intended as a public dedication, regardless of whether such disclosure is expressly recited in the claims.

[0135] Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is embodied by the appended claims. In the claims, 35 U.S.C. 112(f) or 35 U.S.C. 112(6) expressly defines a claim limitation as invoking only when the exact phrase "means for" or "step for" is recited at the beginning of the claim limitation. If such exact phrase is not used in the claim limitation, then neither 35 U.S.C. 112(f) nor 35 U.S.C. 112(6) applies.

[0136] CROSS-REFERENCE TO RELATED APPLICATIONS Under 35 U.S.C. §119(e), this application claims priority to the filing date of U.S. Provisional Patent Application No. 62 / 976,967, filed February 14, 2020, the disclosure of which is incorporated herein by reference.

Claims

1. naloxone free base and a non-aqueous vehicle, substantially free of naloxone N-oxide; A storage-stable non-aqueous topical composition.

2. 10. The storage-stable, non-aqueous topical composition of claim 1, wherein the naloxone free base is present in the composition in an amount ranging from 0.05 to 10% by weight.

3. 3. The storage-stable, non-aqueous topical composition of claim 2, wherein the naloxone free base is present in the composition in an amount ranging from 0.1 to 5% by weight.

4. 4. The storage-stable, non-aqueous topical composition of claim 1, wherein the non-aqueous vehicle comprises a polyethylene glycol component.

5. 5. The storage-stable, non-aqueous topical composition of claim 4, wherein the polyethylene glycol component comprises two or more different polyethylene glycols of different average molecular weights.

6. 6. The storage-stable, non-aqueous topical composition of claim 5, wherein the polyethylene glycol component comprises a first polyethylene glycol having an average molecular weight of 1000 g / mol or less and a second polyethylene glycol having an average molecular weight higher than the first polyethylene glycol.

7. 7. The storage-stable, non-aqueous topical composition of claim 6, wherein the second polyethylene glycol has an average molecular weight of 1000 g / mol or greater.

8. 8. The storage-stable, non-aqueous topical composition of claim 7, wherein the first polyethylene glycol has an average molecular weight of 600 g / mol or less and the second polyethylene glycol has an average molecular weight of 1350 g / mol or more.

9. 9. The storage-stable, non-aqueous topical composition of claim 8, wherein the first polyethylene glycol has an average molecular weight of 300 to 400 g / mol.

10. 10. The storage-stable, non-aqueous topical composition of claim 9, wherein the second polyethylene glycol has an average molecular weight of 1400 to 1500 g / mol.

11. 11. The storage-stable, non-aqueous topical composition of claim 10, comprising 30 to 70% by weight of said first polyethylene glycol.

12. 11. The storage-stable, non-aqueous topical composition of claim 10, comprising more of the first polyethylene glycol than the second polyethylene glycol.

13. 13. The storage-stable, non-aqueous topical composition of claim 12, comprising 30 to 45% by weight of said second polyethylene glycol.

14. 14. The storage-stable, non-aqueous topical composition of any one of claims 6 to 13, wherein, as prepared, at least the first polyethylene glycol component contains 20 ppm or less of peroxide.

15. 1% by weight of naloxone free base and 50-70% by weight of 300-400 g / mol average 15. The storage-stable, non-aqueous topical composition of any one of claims 1 to 14, comprising a first polyethylene glycol having an average molecular weight of 1450 g / ml and 30 to 45% by weight of a second polyethylene glycol having an average molecular weight of 1450 g / ml.

16. 16. The storage-stable, non-aqueous topical composition of any one of claims 1 to 15, which is substantially free of one or more additional impurities.

17. 17. The storage-stable non-aqueous topical composition of claim 16, wherein the one or more additional impurities are selected from the group consisting of RRT 0.32, RRT 0.43, RRT 0.82, RRT 0.86, and RRT 2.

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18. 18. The storage-stable, non-aqueous topical composition of any one of claims 1 to 17, comprising one or more antioxidants.

19. 20. The storage-stable, non-aqueous topical composition of claim 18, wherein the one or more antioxidants are present in an amount ranging from 0.01 to 5.0% w / w.

20. 20. The storage-stable, non-aqueous topical composition of claim 18 or 19, wherein the one or more antioxidants are selected from the group consisting of BHT and propyl gallate.

21. 21. The storage-stable, non-aqueous topical composition of any one of claims 1 to 20, formulated to deliver the naloxone free base locally.

22. 22. The storage-stable, non-aqueous topical composition of any one of claims 1 to 21, formulated to deliver the naloxone free base locally for 2 to 7 hours after application.

23. 23. The storage-stable, non-aqueous topical composition of any one of claims 1 to 22, which is a cream, gel, lotion, or ointment.

24. 24. The storage-stable, non-aqueous topical composition of claim 23, wherein the composition is an ointment.

25. applying to the skin of a subject a storage-stable, non-aqueous topical composition comprising naloxone free base and a non-aqueous vehicle; the composition is substantially free of naloxone N-oxide; method.

26. 26. The method of claim 25, comprising treating or preventing an inflammatory skin disease.

27. 27. The method of claim 26, wherein the inflammatory skin disease is selected from the group consisting of atopic dermatitis, eczema, psoriasis, and combinations thereof.

28. 26. The method of claim 25, comprising treating or preventing a non-inflammatory skin disease.

29. 29. The method of claim 28, wherein the non-inflammatory skin disease is chronic prurigo.

30. 26. The method of claim 25, which comprises treating or preventing pruritus.

31. 31. The method of claim 30, wherein the pruritus is associated with one or more of an inflammatory skin disease, a non-inflammatory skin disease, primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, a neurological condition, or pregnancy.

32. The method of claim 31, wherein the pruritus is drug-induced pruritus or pruritogen-induced pruritus.

33. 33. The method of any one of claims 25 to 32, wherein the composition is formulated to treat or prevent itching associated with a skin condition.

34. The method of any one of claims 25 to 33, wherein the topical composition is applied directly to the locus of the skin condition.

35. 35. The method of claim 34, wherein the topical composition is applied to the skin of the subject in a manner sufficient to cover the entire skin condition.

36. 36. The method of any one of claims 25 to 35, wherein the topical composition is maintained in contact with the skin of the subject for one hour or more.

37. 37. The method of any one of claims 25 to 36, wherein the topical composition is maintained in contact with the skin of the subject for 2 to 7 hours.

38. 38. The method of any one of claims 25 to 37, wherein the naloxone free base is present in the composition in an amount ranging from 0.05 to 10% by weight.

39. 39. The method of claim 38, wherein the naloxone free base is present in the composition in an amount ranging from 0.1 to 5% by weight.

40. 40. The method of any one of claims 25 to 39, wherein the non-aqueous vehicle comprises a polyethylene glycol component.

41. 41. The method of claim 40, wherein the polyethylene glycol component comprises two or more different polyethylene glycols of different average molecular weights.

42. 42. The method of claim 41 , wherein the polyethylene glycol component comprises a first polyethylene glycol having an average molecular weight of 1000 g / mol or less and a second polyethylene glycol having an average molecular weight higher than the first polyethylene glycol.

43. 43. The method of claim 42, wherein the second polyethylene glycol has an average molecular weight of 1000 g / mol or greater.

44. 44. The method of claim 43, wherein the first polyethylene glycol has an average molecular weight of 600 g / mol or less and the second polyethylene glycol has an average molecular weight of 1350 g / mol or more.

45. 45. The method of claim 44, wherein the first polyethylene glycol has an average molecular weight of 300 to 400 g / mol.

46. 46. ​​The method of claim 45, wherein the second polyethylene glycol has an average molecular weight of 1400 to 1500 g / mol.

47. 47. The method of claim 46, wherein the composition comprises 30 to 70% by weight of the first polyethylene glycol.

48. 48. The method of claim 47, wherein the composition comprises more of the first polyethylene glycol than the second polyethylene glycol.

49. 49. The method of claim 48, wherein the composition comprises 30 to 45% by weight of the second polyethylene glycol.

50. 50. The method of any one of claims 42 to 49, wherein at least the first polyethylene glycol component contains 20 ppm or less of peroxide at the time the composition is prepared.

51. 51. The method of any one of claims 25 to 50, wherein the composition comprises 1% by weight of naloxone free base, 50 to 70% by weight of a first polyethylene glycol having an average molecular weight of 300 to 400 g / mol, and 30 to 45% by weight of a second polyethylene glycol having an average molecular weight of 1450 g / ml.

52. 52. The method of any one of claims 25 to 51, wherein the composition is substantially free of one or more additional impurities.

53. 53. The method of claim 52, wherein the one or more additional impurities are selected from the group consisting of RRT 0.32, RRT 0.43, RRT 0.82, RRT 0.86, and RRT 2.

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54. 54. The method of any one of claims 25 to 53, wherein the composition comprises one or more antioxidants.

55. 55. The method of claim 54, wherein the one or more antioxidants are present in an amount ranging from 0.01 to 5.0% w / w.

56. 56. The method of claim 54 or 55, wherein the one or more antioxidants are selected from the group consisting of BHT and propyl gallate.

57. 57. The method of any one of claims 25 to 56, wherein the composition is formulated to deliver the naloxone free base locally.

58. 58. The method of any one of claims 25 to 57, wherein the composition is formulated to deliver the naloxone free base locally for 2 to 7 hours after application.

59. 59. The method of any one of claims 25 to 58, wherein the composition is a cream, gel, lotion, or ointment.

60. 60. The method of claim 59, wherein the composition is an ointment.

61. A kit comprising: a storage-stable non-aqueous topical composition according to any one of claims 1 to 24; Dispensing Devices and A kit comprising:

62. 62. The kit of claim 61, wherein the dispensing device comprises a tube.

63. 63. The kit of claim 62, wherein the tube comprises a squeezable tube.

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