Topical naloxone compositions and methods of use thereof

Abstract

Aspects of the invention include topical naloxone compositions for topical delivery of naloxone to the skin of a subject. The topical composition according to certain embodiments is a storage stable non-aqueous topical composition comprising a naloxone free base and a non-aqueous solvent wherein the composition is substantially free of naloxone N-oxide. The invention also provides a method for locally delivering naloxone to a subject by using the external use composition, and a kit containing the external use naloxone composition.

Description

[0001] Divisional Application Instructions This patent application is a divisional application of Chinese patent application No. 2021800276306, filed on February 11, 2021, entitled “Topical Naloxone Composition and Method of Using Thereof”.

[0002] Cross-references to related applications Pursuant to Section 119(e) of Chapter 35 of the United States Code, this patent application claims priority to the filing date of U.S. Provisional Patent Application No. 62 / 976,967, filed on February 14, 2020, the contents of which are incorporated herein by reference. Technical Field

[0003] This invention generally relates to the treatment of skin diseases, and in particular, to topical naloxone compositions and methods of using thereof. Background Technology

[0004] Naloxone is a narcotic μ-opioid receptor (MOR) antagonist with a high affinity for μ-opioid receptors in the central nervous system. μ-opioid receptors are a class of opioid receptors with affinity for enkephalins and β-endorphins, but lower affinity for dynorphins. The three well-characterized variants of μ-opioid receptors are μ1, μ2, and μ3, which are commonly found presynaptic (e.g., in the periaqueductal gray area and superficial dorsal horn of the spinal cord) or postsynaptic. Activation of μ-opioid receptors (e.g., using agonists) can cause analgesia, sedation, hypotension, pruritus, nausea, euphoria, decreased respiration, and pupillary constriction. μ-opioid receptors are also found in the gut, and activation of these receptors can sometimes inhibit intestinal motility, leading to constipation. Naloxone (commercially also known as Narcan® or Evzio®) also has low affinity for κ-opioid and δ-opioid receptors.

[0005] Naloxone is typically administered parenterally (e.g., intravenous injection or infusion), a route that allows for rapid drug delivery and complete bioavailability, making the route predictable and controllable. Parenterally administered liquid formulations must be sterile and free of particulate matter. To predict efficacy and safety, these formulations must exhibit good physical and chemical stability. Summary of the Invention

[0006] Aspects of the present invention include topical naloxone compositions for the local delivery of naloxone to the skin of a subject. The topical compositions according to certain embodiments are storage-stable, non-aqueous topical compositions comprising a free naloxone base and a non-aqueous solvent, wherein said compositions are substantially free of naloxone N-oxide. The present invention also provides methods for using said topical compositions to locally deliver naloxone to a subject, and kits containing said topical naloxone compositions. Attached Figure Description

[0007] Figures 1 and 2 show the observed percentage of naloxone N-oxide in each of the various ointment formulations prepared using different PEG sources.

[0008] Figure 3 depicts the average number of scratches and cumulative scratch duration on days 34 and 41 in mice treated with the following: 1) placebo (without naloxone active agent); 5 or 2) topical composition with free naloxone base.

[0009] Figure 4 depicts the average number of scratches and cumulative scratching duration on days 48 and 55 in mice treated with the following: 1) placebo (without naloxone active agent); 5 or 2) topical composition with free naloxone base.

[0010] Figure 5 depicts the average number of scratches and cumulative scratching duration on days 34 and 41 in mice treated with the following: 1) placebo (without naloxone active agent); or 2) topical composition containing naloxone hydrochloride.

[0011] Figure 6 depicts the average number of scratches and cumulative scratching duration on days 48 and 55 in mice treated with the following: 1) placebo (without naloxone active agent); or 2) topical composition containing naloxone hydrochloride.

[0012] Figures 7A-7C depict the transdermal water loss observed on days 34, 48, and 55 in the placebo (without naloxone active agent) composition group and the topical composition group with naloxone free base.

[0013] Figures 8A-8B depict the transdermal water loss observed on days 33 and 55 in the placebo (without naloxone active agent) composition group and the topical composition group with naloxone hydrochloride.

[0014] Figures 9A-9B depict example photographs of mouse skin after administration of a placebo (without naloxone active agent) composition and a topical composition having a free naloxone base and a hydrophobic delivery solvent.

[0015] Figures 10A-10B depict example photographs of mouse skin after administration of a placebo (without naloxone active agent) composition and a topical composition having naloxone hydrochloride and a hydrophilic delivery solvent containing only polyethylene glycol. Detailed Implementation

[0016] Aspects of the present invention include topical naloxone compositions for the local delivery of naloxone to the skin of a subject. The topical compositions according to certain embodiments are storage-stable, non-aqueous topical compositions comprising a free naloxone base and a non-aqueous solvent, wherein said compositions are substantially free of naloxone N-oxide. The present invention also provides methods for using said topical compositions to locally deliver naloxone to a subject, and kits containing said topical naloxone compositions.

[0017] Before describing the invention in more detail, it should be understood that the invention is not limited to the specific embodiments described, as differences will certainly exist in actual implementation. It should also be understood that the terminology used herein is for describing specific embodiments only and is not intended to limit the inventive concept; the scope of the invention will be defined only by the appended claims.

[0018] When a numerical range is provided, it should be understood that every intermediate value between the upper and lower limits of the range, as well as any other specified value or intermediate value within that range, is included within the scope of this invention. Unless the context explicitly specifies otherwise, each intermediate value should be as low as one-tenth of the lower limit unit. The upper and lower limits of these smaller ranges may be independently included within the smaller range and also within this invention, subject to the requirements of any specifically excluded limits within the range. Where the range includes one or two limits, the range excluding any one or both of the included limits is also included within this invention.

[0019] Certain ranges presented in this paper are preceded by the term "approximately". The purpose of using the term "approximately" in this paper is to provide textual support for the precise figures that follow and for figures that are close to or approximate to the figures following the term. In determining whether a figure is close to or approximate to a specifically listed figure, an unlisted figure that is close to or approximates can be substantially equivalent to the specifically listed figure in its context.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although similar or equivalent methods and materials may be used in the implementation or testing of this invention, representative exemplary methods and materials are described below.

[0021] All publications and patents referenced in this specification are incorporated herein by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, and the purpose of their inclusion is to disclose and describe methods and / or materials relating to the cited publications. References to any publication refer to its content disclosed prior to the filing date and should not be construed as an admission that the present invention is not entitled to precede such publication by prior invention. Furthermore, the publication dates provided may differ from the actual publication dates and may require separate verification.

[0022] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly indicates otherwise. It should also be noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a precondition for the use of specialized terms related to the stated elements of a claim, such as “alone,” “only,” or the use of the limiting word “negative.”

[0023] Upon reading this invention, the following will be apparent to those skilled in the art: each individual embodiment described and listed herein has hierarchical components and features that can be quickly decomposed or combined with features of any of the other embodiments without departing from the scope and spirit of the invention. Any of the stated methods may be implemented in the order of the stated events or in any other logically possible order.

[0024] Although the device and method have been or will be described and their functions explained for grammatical fluency, it should be clearly understood that, unless expressly provided for in Chapter 35 of the United States Code, the claims shall not in any case be construed as necessarily being limited to “method” or “step,” but shall conform to the judicial principles of equivalence and the meaning and full scope of the equivalent as defined in the claims. When the claims are explicitly drafted in accordance with the provisions of Section 112 of Chapter 35 of the United States Code, the claims shall conform in full to the legal equivalents in Section 112 of Chapter 35 of the United States Code.

[0025] In further describing various embodiments of the invention, the various aspects of the topical composition are first reviewed in more detail, followed by a detailed description of an embodiment of using the topical composition to deliver naloxone to a subject for the treatment of a skin condition, and a review of a kit comprising the target topical naloxone composition.

[0026] Topical Composition As described above, aspects of the present invention include a topical composition for delivering a measured amount of naloxone free base to a subject. Therefore, the topical composition comprises naloxone free base. The structural formula of the naloxone free base is shown below:

[0027] In the embodiments, the target naloxone composition is formulated for transsurface delivery of the naloxone free base to a subject. As used herein, the term "transsurface delivery" refers to a route of administration in which the naloxone free base is delivered across the skin surface, such as to one or more of the subcutaneous tissue, dermis, and epidermis, including the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale. Therefore, a topical composition having the naloxone free base is formulated for application to any suitable location, such as the arms, legs, buttocks, abdomen, back, neck, scrotum, face, behind the ears, etc. In some embodiments, the skin is healthy and intact. In other embodiments, the skin may be one or more layers (e.g., stratum corneum, stratum germinativum, stratum spinosum, stratum basale, etc.) of skin that may be diseased, inflamed, or not completely intact. As used herein, the term "incompletely intact" means that one or more layers of incompletely intact skin include at least one perforation caused by lesions, inflammation, or other problems. Incompletely intact skin may include barrier function defects (e.g., perforations) in one or more layers of said skin, such as in the stratum corneum, with a cumulative area of ​​0.01% or more of the surface area to which the topical naloxone composition is administered, for example, 0.05% or more, 0.1% or more, 0.5% or more, 1% or more, 2% or more, 3% or more, 5% or more, 10% or more, 25% or more, 50% or more, 75% or more, 90% or more, 95% or more, 97% or more, and 99% or more.

[0028] In some embodiments, the naloxone free base is locally delivered to the administration site. As used herein, the term "locally" means delivery of naloxone near or potentially near the administration site. In these embodiments, the naloxone free base diffuses from the administration site a predetermined distance, such as 30 cm or less, 25 cm or less, 20 cm or less, 15 cm or less, 10 cm or less, 5 cm or less, 4 cm or less, 3 cm or less, 2 cm or less, 1 cm or less, 0.5 cm or less, and including 0.1 cm or less. In other words, in these embodiments, the target composition is applied via the body surface to deliver naloxone to the administration site or a location a short distance from the administration site. The penetration depth of the naloxone free base into the skin at the application site can vary depending on the composition of the hydrophilic delivery solvent (described below), and the penetration depth can be from 0.01 mm to 15 mm, for example 0.05 mm to 14.5 mm, 0.1 mm to 14 mm, 0.5 mm to 13.5 mm, 1 mm to 13 mm, 1.5 mm to 12.5 mm, 2 mm to 12 mm, 2.5 mm to 11.5 mm, 3 mm to 11 mm, 3.5 mm to 10.5 mm, 4 mm to 10 mm, and includes a penetration depth of 5 mm to 10 mm into the skin at the application site. In some cases, the administration method described above can also achieve systemic administration of naloxone, such as low-dose systemic administration of naloxone.

[0029] In some embodiments, the intended topical composition is formulated to prolong the delivery of naloxone to the subject. As used herein, the term "prolonged delivery" means that the composition is formulated to deliver naloxone over a longer period of time, such as several hours, including 1 hour or longer, such as 2 hours or longer, 3 hours or longer, 4 hours or longer, 5 hours or longer, 6 hours or longer, 7 hours or longer. For the above time ranges, in some cases, the upper limit of the time period is 10 hours or less, such as 9 hours or less, 8 hours or less, 7 hours or less. In some embodiments, the topical composition is formulated to deliver naloxone to the subject over a period of time, such as 1 to 10 hours, 2 hours to 9 hours, or 2 hours to 7 hours.

[0030] Depending on the application site and physiological function of the subject, as well as the application surface area of ​​the naloxone composition on the skin, the amount of free naloxone base in the targeted topical composition may vary. In some cases, the amount of naloxone ranges from 0.01 mg to 2000 mg, for example, 0.02 mg to 1750 mg, 0.03 mg to 1500 mg, 0.04 mg to 1250 mg, 0.05 mg to 1000 mg, 0.06 mg to 750 mg, 0.07 mg to 500 mg, 0.08 mg to 250 mg, 0.09 mg to 100 mg, and includes 0.01 mg to 50 mg. In some embodiments, the amount of free base ranges from 1 mg to 200 mg, for example, 2.5 mg to 175 mg, 5 mg to 150 mg, 7.5 mg to 125 mg, and includes 10 mg to 100 mg. In some embodiments, the amount of the naloxone free base is 0.01% w / w to 15% w / w of the total weight of the topical composition, for example, 0.05% w / w to 12.5% ​​w / w, 0.05% w / w to 10% w / w, including 0.1% w / w to 10% w / w, for example, 0.1% w / w to 5% w / w, including 0.5% w / w to 5% w / w, for example, 0.75% w / w to 2.5% w / w. 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.

[0031] Furthermore, the composition is substantially free of naloxone N-oxide. The molecular formula of naloxone N-oxide is: C 19 H 21 NO5, its structural formula is shown below:

[0032] Since the composition is substantially free of naloxone N-oxide, the amount of naloxone N-oxide (if present) in the composition is 0.5% w / w or less, for example 0.2% w / w or less, and includes 0.1% w / w or less. In some cases, the composition includes undetectable naloxone N-oxide, which makes it undetectable in the formulation when using the protocols described in the “Experimental” section below.

[0033] In some cases, the composition is a storage-stable composition. Even after storage under storage conditions (e.g., aseptic packaging conditions at room temperature) for a period of time (e.g., more than one month, such as three months or longer, including six months or longer, such as 12 months or longer), the storage-stable compositions of the embodiments of the present invention are substantially free of naloxone N-oxide. In some cases, the topical formulation is a storage-stable formulation in which the properties of the composition and / or the active agent (e.g., color, viscosity, active agent activity, etc.) are not substantially altered at room temperature and high temperatures (e.g., 40°C or higher, including 50°C or higher) over extended periods of time (e.g., one week or longer, two weeks or longer, one month or longer, six months or longer, one year or longer).

[0034] The topical composition according to embodiments of the present invention comprises a non-aqueous topical delivery solvent. "Topical delivery solvent" refers to a composition that carries and allows the free naloxone base to contact and penetrate the skin of a subject. In the embodiments, the intended topical composition is a non-aqueous composition. Because the topical delivery solvent is non-aqueous, it does not contain water, for example, as a solvent. Therefore, the solvent (comprising the composition of the solvent and the free naloxone base) does not contain water.

[0035] In some cases, the non-aqueous solvent includes a polyethylene glycol component. As used herein, the term "polyethylene glycol" refers to a polymeric compound having an ethylene oxide backbone structure, such as linear polyethylene glycol, branched polyethylene glycol, functionalized linear polyethylene glycol, or multifunctionalized branched polyethylene glycol, or any combination thereof.

[0036] The intended topical delivery solvent composition comprises a polyethylene glycol component having an average molecular weight (e.g., the molecular weight specified in the United States Pharmacopeia) of 100 g / mol to 7500 g / mol, such as 150 g / mol to 5000 g / mol, 200 g / mol to 2500 g / mol, or 300 g / mol to 1500 g / mol. In its conventional sense, the term "average molecular weight" refers to the total weight of the polymer divided by the total number of molecules. In some embodiments, the polyethylene glycol component comprises polyethylene glycol with 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 method, including but not limited to titration, size exclusion chromatography, high-performance liquid chromatography, gel permeation chromatography, mass spectrometry, etc.

[0037] The polyethylene glycol (PEG) component may include one or more different types of PEG, such as two or more different types of PEG, three or more different types of PEG, four or more different types of PEG, five or more different types of PEG, and ten or more different types of PEG. In some embodiments, the PEG component in the target naloxone composition includes a first PEG and a second PEG. In some such embodiments, the PEG component may include a first PEG (e.g., PEG600 and PEGs with a molecular weight below 600) that is liquid at below room temperature (RT) and a second PEG (e.g., PEG1000 and PEGs with a molecular weight above 1000) that is a waxy solid at room temperature or above RT. In some embodiments, the first PEG component is a lower molecular weight PEG with an average molecular weight of 1000 g / mol or less, while the second PEG component is a higher molecular weight PEG with an average molecular weight of 1000 g / mol or greater. For example, the first polyethylene glycol component may be a polyethylene glycol with an average molecular weight of 600 g / mol or less (e.g., 550 g / mol or less, 500 g / mol or less, 450 g / mol or less, 400 g / mol or less, 350 g / mol or less, 300 g / mol or less). For example, the first polyethylene glycol component may be a polyethylene glycol with an average molecular weight ranging from 200 g / mol to 600 g / mol (e.g., 250 g / mol to 500 g / mol, 300 g / mol to 400 g / mol). In some embodiments, the first polyethylene glycol component is a polyethylene glycol with an average molecular weight of 300 g / mol. In some embodiments, the first polyethylene glycol component is a polyethylene glycol with an average molecular weight of 400 g / mol. The second polyethylene glycol component may be polyethylene glycol with an average molecular weight of 1000 g / mol or greater (e.g., 1050 g / mol or greater, 1100 g / mol or greater, 1150 g / mol or greater, 1200 g / mol or greater, 1250 g / mol or greater, 1300 g / mol or greater, 1350 g / mol or greater, 1400 g / mol or greater, 1450 g / mol or greater), and includes polyethylene glycol with an average molecular weight of 1500 g / mol or greater.For example, the second polyethylene glycol component may be polyethylene glycol with an average molecular weight ranging from 1000 g / mol to 6000 g / mol (e.g., 1100 g / mol to 4000 g / mol, 1200 g / mol to 3000 g / mol, 1300 g / mol to 2000 g / mol, and including 1400 g / mol to 1500 g / mol). In some embodiments, the second polyethylene glycol component is polyethylene glycol with an average molecular weight of 1450 g / mol. The percentage of the first molecular weight (e.g., 300 or 500 g / mol) polyethylene glycol may vary depending on the total amount of polyethylene glycol present, and in some cases, the percentage ranges from 20% to 90%, for example, 30% to 70%, including 50% to 70%. The percentage of the second molecular weight (e.g., 1450 g / mol) polyethylene glycol can vary, and in some cases, the percentage ranges from 20% to 50%, for example, 30% to 45%. In the case of a combination of a first lower molecular weight polyethylene glycol and a second higher molecular weight polyethylene glycol, the composition comprises more of the first polyethylene glycol than the second polyethylene glycol; for example, the amount of the first lower molecular weight polyethylene glycol may exceed the amount of the second higher molecular weight polyethylene glycol, for example, by 2% or more, for example, 5% or more, including 10% or more.

[0038] In some cases, the storage-stable non-aqueous topical composition comprises 0.1% to 1% (by weight) of naloxone free base, 50% to 70% (by weight) of a first polyethylene glycol (average molecular weight 300 to 400 g / mol), and 30% to 45% (by weight) of a second polyethylene glycol (average molecular weight 1450 g / ml). The target formulation includes: 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.

[0039] In some embodiments, the polyethylene glycol is a pharmaceutical-grade polyethylene glycol having a molecular weight certified by regulatory agencies (e.g., the United States Pharmacopeia, USP and National Formulary, European Pharmacopoeia, etc.) (i.e., with a test report). In some cases, at least the first polyethylene glycol component is a polyethylene glycol that contains little or no peroxides in the preparation of the composition, for example, 50 ppm or less, such as 40 ppm or less, including 30 ppm or less, 20 ppm or less, 10 ppm or less, 5 ppm or less, 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); Improve® Millipore polyethylene glycol (Merck KGaA, Darmstadt, Germany); Pluriol® polyethylene glycol (BASF); Macrogol polyethylene glycol (NOF Corporation, Japanese Pharmacopoeia); and so on.

[0040] If desired, the non-aqueous delivery solvent may include one or more antioxidants. The amount of the one or more antioxidants may vary, and in some cases, the amount ranges from 0.01% w / w to 5.0% w / w, for example, from 0.02% w / w to 2.0% w / w. Any suitable antioxidant capable of reducing the occurrence of impurities may be present, such as the antioxidants described in the Experimental Section below, examples of which include: butylated hydroxytoluene (BHT); propyl gallate; etc.

[0041] The amount of non-aqueous delivery solvent (e.g., PEG) present in the topical naloxone composition can vary, and the amount can range from 90% w / w to 99.9% w / w, for example, 95% w / w to 99.9% w / w, 99% w / w to 99.9% w / w.

[0042] The topical naloxone composition can be varied as needed. In some cases, the topical naloxone composition is an ointment. The term "ointment" refers to a semi-solid dosage form intended for external application to the skin or mucous membranes. In some cases, the ointment exhibits a drying loss rate of 25% or less, for example, 20% or less. In some cases, the ointment exhibits a viscosity range of 300,000 to 2,000,000 cp, for example, 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" refers to a semi-solid dosage form containing one or more active pharmaceutical ingredients dissolved or dispersed in a suitable matrix. In some cases, the cream exhibits a viscosity range of 25,000 to 900,000 cp, for example, 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 a topical suspension, solution, or emulsion intended for application to the skin. In some cases, the lotion exhibits a drying loss rate of 40% or more, for example, 50% or more. In some cases, the lotion is pourable and exhibits a viscosity range of 1,000 to 50,000 cp, for example, 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 semi-solid system consisting of a suspension (which is composed of small inorganic particles) or large organic molecules permeated by a liquid. In some cases, the gel exhibits a drying loss rate of 60% or more, such as 70% or more. In some cases, the gel exhibits a viscosity of 5,000 to 100,000 cp, such as 5,000 to 70,000 cp. In some cases, the topical naloxone composition is formulated as a liquid and can be dispensed as a spray, aerosol, or foam.

[0043] The topical naloxone composition according to embodiments of the present invention is non-irritating to the skin of the subject at the application site. Generally speaking, skin irritation as used herein refers to adverse skin reactions, discoloration, or damage, such as redness (erythema), pain, itching, swelling (edema), or dryness. Therefore, the target topical composition is formulated such that when applied to the skin of the subject, skin quality remains normal, and local delivery of naloxone is consistent throughout the dosing interval.

[0044] 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.

[0045] In some embodiments, the target topical naloxone composition may be first applied to a patch, which is then applied to the skin site of the subject, or the patch may be placed on the surface of the skin site to which the topical naloxone composition has been applied. The patch may be made of a material that does not absorb naloxone. Target patches include, but are not limited to, nonwoven fabrics, woven fabrics, films (including sheets), porous materials, foam materials, paper, nonwoven fabrics or woven / film laminates, and combinations thereof. Nonwoven fabrics 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. Woven fabrics may include cotton, rayon, polyacrylic resin, polyester resin, polyvinyl alcohol, and combinations thereof. The film 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 also includes cellophane, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluoropolymers, styrene-isoprene-styrene copolymer, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymer, polyamide, and polysulfone; and combinations thereof. The paper may include impregnated paper, coated paper, pulpless paper, kraft paper, washi paper, cellophane, synthetic paper, and combinations thereof. In some embodiments, the patch is a closing material.

[0046] The size of the patch can vary depending on the application area of ​​the topical naloxone composition on the skin, and in some cases, the patch size can cover the entire application site of the subject. Therefore, the length of the patch can range from 2 to 100 cm, for example, 4 to 60 cm, and its width can range from 2 to 100 cm, for example, 4 to 60 cm. The surface area of ​​the target patch can range from 4 cm². 2 Up to 1000 cm 2 For example, 5 cm 2 Up to 500cm 2 10 cm 2 Up to 250 cm 2 15 cm 2 Up to 100 cm 2 And including 20 cm 2 Up to 50 cm 2 .

[0047] Method of application of topical naloxone composition The invention also includes a method of administering a topical naloxone composition to a subject. As described above, "topical" refers to a route of administration in which naloxone is delivered through the skin, for example, to one or more of the subcutaneous tissue, dermis, and epidermis, including the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale. Therefore, the method may include applying the target naloxone composition to a skin site such as the arm, leg, buttock, shoulder, hip, thigh, abdomen, back, neck, scrotum, face, behind the ear, etc. In some embodiments, the method includes applying the target composition to healthy and intact skin. In other embodiments, the method includes applying the target composition to skin in one or more layers (e.g., the stratum corneum, stratum germinativum, stratum spinosum, stratum basale, etc.) where there may be lesions, inflammation, or incomplete integrity, such as skin in one or more layers that includes barrier function defects (e.g., perforations), such as defects in the stratum corneum caused by lesions, inflammation, or other problems. For example, the method may include application to the skin surface of a subject, wherein the skin includes barrier function defects (e.g., perforations) in one or more layers, the cumulative area of ​​which is 0.01% or more of the surface area to which the topical naloxone composition is administered, such as 0.05% or more, 0.1% or more, 0.5% or more, 1% or more, 2% or more, 3% or more, 5% or more, 10% or more, 25% or more, 50% or more, 75% or more, 90% or more, 95% or more, 97% or more, and 99% or more of the surface area to which the topical naloxone composition is administered.

[0048] In describing the methods of the present invention, the term "subject" refers to a person or organism to which the topical composition is applied and which remains in continuous contact with the topical composition. Therefore, the subject of the present invention can include, but is not limited to, mammals such as humans and other primates, such as chimpanzees, other apes and monkeys, dogs, rabbits, cats, and other domestic pets, wherein in some embodiments, the subject is a human. The term "subject" also includes any person or organism of any age, weight, or other physical characteristic, wherein the subject can be an adult, child, infant, or newborn.

[0049] As described above, the method of the present invention includes applying a topical naloxone composition to the skin surface of a subject and contacting the topical naloxone composition with the subject for a period of time sufficient to deliver naloxone to the subject. In some embodiments, the method includes extending the time of delivery of naloxone to the skin site of the subject. “Extended transdermal delivery” means that the topical composition is formulated to deliver naloxone over a longer period of time, such as several hours, including 1 hour or longer, such as 2 hours or longer, 3 hours or longer, 4 hours or longer, 5 hours or longer, and including 6 hours or longer, such as 7 hours or longer. For example, the topical composition may be formulated to deliver naloxone to the skin site of the subject for a duration of 0.1 hours to 20 hours, such as 0.5 hours to 15 hours, 1 hour to 10 hours, 2 hours to 7 hours.

[0050] In some embodiments, the regimen may include multiple dosing intervals. "Multiple dosing intervals" refers to sequentially applying two or more doses of the topical composition and keeping it in continuous contact with the subject. Therefore, the first application of the topical composition is removed (e.g., washed off with water or wiped clean with a damp cloth), and a second dose of the topical composition is applied to the subject's skin surface. When implementing the method of the invention, the treatment regimen may include two or more dosing intervals, for example, three or more dosing intervals, four or more dosing intervals, five or more dosing intervals, including ten or more dosing intervals.

[0051] In treatment regimens with multiple dosing intervals, the duration between different dosing intervals may vary, depending on the subject's physiological function or the treatment protocol devised by healthcare professionals. For example, in a multiple-dose treatment regimen, the duration between different dosing intervals may be predetermined and use fixed time intervals. Therefore, the duration between different dosing intervals may vary, possibly being 1 hour or longer, such as 2 hours or longer, 4 hours or longer, 6 hours or longer, 8 hours or longer, 12 hours or longer, 16 hours or longer, and including 24 hours or longer. In some embodiments, in regimens with multiple dosing intervals, the duration between different dosing intervals is 1 day or longer, such as 2 days or longer, 3 days or longer, 4 days or longer, 5 days or longer, 6 days or longer, 7 days or longer, 10 days or longer, including 30 days or longer. In some cases, the maximum time between different dosing intervals is 30 days or less, such as 28 days or less, 21 days or less, 14 days or less, 7 days or less, and including 3 days or less. In some embodiments, the time range between different dosing intervals may be 2 to 30 days, 3 to 28 days, 4 to 21 days, 5 to 14 days, etc., and including 6 to 10 days. In some cases, the duration between different dosing intervals may depend on the progress of treatment for a specific condition (see below), skin irritation, dry skin, or the degree of symptom relief for the treated condition (e.g., relief of itching).

[0052] According to certain embodiments, methods for applying a topical naloxone composition and maintaining it in continuous contact with a subject can be used to treat or prevent skin conditions such as inflammatory skin diseases, non-inflammatory skin diseases, pruritus, or one or more symptoms associated with inflammatory skin diseases, non-inflammatory skin diseases, or pruritus. For example, in some cases, the method includes applying the topical composition to the skin surface of a subject to treat or prevent inflammatory skin diseases such as atopic dermatitis, eczema, psoriasis, or combinations thereof. In other cases, the method includes applying the topical composition to the skin surface of a subject to treat or prevent non-inflammatory skin diseases such as chronic prurigo. In still other cases, the method includes treating or preventing pruritus via the body surface by applying one or more of the above-described topical naloxone compositions to the skin of a subject. In some 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 disorders, or pregnancy. In some embodiments, the pruritus is drug-induced pruritus or pruritus induced by pruritogens. In some embodiments, the pruritus is associated with a condition selected from herpes zoster, psoriasis, urticaria, paresthesia, Gover's disease, chronic kidney disease, and Hailey-Hailey's disease. The pruritus may be accompanied by skin redness, skin bumps, plaques or vesicles, dry or cracked skin, leathery skin, or scaly skin, and the method may further include administering a targeted naloxone composition in an amount sufficient to treat one or more of the skin redness, skin bumps, plaques or vesicles, dry or cracked skin, leathery skin, or scaly skin associated with the pruritus.

[0053] According to some embodiments, in methods of treating skin conditions, the topical naloxone composition may be applied directly to the affected area of ​​the skin (e.g., the location of an inflammatory skin condition, a non-inflammatory skin condition, or pruritus). The topical composition may be applied to all or part of the affected area, such as 5% or more of the affected area, for example, 10% or more, 25% or more, 50% or more, 75% or more, 90% or more, 95% or more, and including 99% or more. In some cases, the topical composition is applied to the entire affected area. In some cases, the topical composition is applied to an area larger than the affected area, such as a portion of the skin surface immediately adjacent to the affected area, for example, an additional 5% (based on the size of the affected skin) or more of the surrounding skin area, for example, an additional 10% or more, an additional 15% or more, and including an additional 25% or more of the surrounding skin area.

[0054] In its conventional sense, the term "treatment" as used herein refers to at least one improvement in the symptoms associated with the subject's disease, where improvement is broadly defined as a decrease in the degree of a parameter (e.g., symptoms) related to the treated disease. Therefore, treatment also includes the complete resolution of the pathological state or at least the associated symptoms, resulting in the subject no longer having the disease or at least no longer experiencing symptoms characteristic of the disease. In its conventional sense, the term "management" as used herein refers to at least the control of the symptoms associated with the subject's disease (i.e., the degree of symptoms is maintained within a predetermined level), and in some cases, improvement of the symptoms without resolution of the underlying disease.

[0055] As used herein, the term "prevention" refers to reducing or completely eliminating the likelihood of a disease occurring. For example, applying a target topical composition to the skin surface of a subject for the purpose of disease prevention, thereby preventing the occurrence of a skin condition or its associated symptoms or reducing their severity. Therefore, according to some embodiments, the method includes applying a target topical naloxone composition for prevention purposes sufficient to reduce the severity of the condition or its associated symptoms by 5% or more, for example, 10% or more, 15% or more, 25% or more, 50% or more, 75% or more, 90% or more, 95% or more, and 99% or more, as determined by a qualified healthcare professional (e.g., based on the size of the affected skin, the level of inflammation, etc.). In some embodiments, applying a topical naloxone composition according to the target method is sufficient to completely eliminate the occurrence of the condition or any symptoms associated with the skin disease. In some embodiments, applying the topical naloxone composition to the skin surface of the subject for preventative purposes is sufficient to shorten the duration of the skin condition, for example, by 0.1 days or longer, 0.5 days or longer, 1 day or longer, 2 days or longer, 3 days or longer, 4 days or longer, 5 days or longer, 6 days or longer, 7 days or longer, and including 14 days or longer. In other embodiments, applying the topical naloxone composition to the skin surface of the subject for preventative purposes is sufficient to reduce the severity of symptoms associated with the skin condition, such as itching. For example, applying the topical naloxone composition to the skin surface of the subject for preventative purposes may be sufficient to reduce the number of times the skin surface is scratched due to the skin condition by 1 or more times per hour, for example, 2 or more times, 3 or more times, 5 or more times, 10 or more times, 15 or more times, 25 or more times, 50 or more times, and including 100 or more times. In cases where the method includes treating pruritus for preventative purposes, the topical naloxone composition may be applied to the subject’s skin surface 1 hour or longer before the onset of symptoms associated with said pruritus (e.g., itching, redness, scaling, blisters, or bumps), for example 3 hours or longer, 6 hours or longer, 12 hours or longer, and including 24 hours or longer before the onset of symptoms.

[0056] In embodiments, the topical composition may be applied to the subject’s skin surface for preventative purposes one hour or longer before the expected occurrence of skin conditions or related symptoms (e.g., pruritus caused by a drug or pruritogen), for example, two hours or longer, four hours or longer, six hours or longer, eight hours or longer, twelve hours or longer, sixteen hours or longer, twenty hours or longer, twenty-four hours or longer, and including for 48 hours or longer.

[0057] In some embodiments, the method includes applying a topical naloxone composition to the skin surface of a subject while treating or preventing 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 disorders, or pregnancy, or may be drug-induced pruritus or pruritus caused by pruritogens. In some embodiments, the naloxone composition is formulated to treat or prevent one or more of the following skin redness, bumps, patches or blisters, dry or cracked skin, leathery skin, or scaly skin associated with the pruritus. In these embodiments, application of the topical naloxone composition is sufficient to reduce the severity of the pruritus, for example, by 5% or more (e.g., based on a patient-response questionnaire, the number of times the skin surface is scratched within a predetermined time period), such as 10% or more, 15% or more, 25% or more, 50% or more, 75% or more, 90% or more, 95% or more, and including 99% or more. In some cases, application of the topical naloxone composition and its continuous contact with the skin surface is sufficient to eliminate the pruritus. For example, application of the topical naloxone composition to the subject is sufficient to reduce the number of times the skin surface is scratched due to the pruritus by one or more times per hour, such as two or more, three or more, five or more, ten or more, fifteen or more, twenty-five or more, fifty or more, and including 100 or more times per hour. In cases where the method includes treating pruritus for preventative purposes, the topical naloxone composition may be applied to the subject’s skin surface 1 hour or longer before the onset of symptoms associated with said pruritus (e.g., itching), such as 3 hours or longer, 6 hours or longer, 12 hours or longer, and including 24 hours or longer before the onset of symptoms.

[0058] In other embodiments, the method includes applying a topical naloxone composition to the skin surface of a subject while treating or preventing an inflammatory skin condition such as atopic dermatitis, eczema, or psoriasis. In some 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 an inflammatory skin condition, such as pruritus caused by atopic dermatitis, eczema, or psoriasis. In these embodiments, application of the topical naloxone composition is sufficient to reduce the severity of symptoms associated with the inflammatory skin condition (e.g., pruritus), for example, by 5% or more (e.g., based on a patient-response questionnaire, the number of times the skin surface was scratched within a predetermined time period), such as 10% or more, 15% or more, 25% or more, 50% or more, 75% or more, 90% or more, 95% or more, and including 99% or more. In some cases, applying the topical naloxone composition and maintaining it in continuous contact with the skin surface is sufficient to eliminate symptoms associated with the inflammatory skin condition (e.g., itching). For example, applying the topical naloxone composition to the subject is sufficient to reduce the number of times the skin surface is scratched due to itching caused by the inflammatory skin condition by one or more times per hour, such as two or more, three or more, five or more, ten or more, fifteen or more, twenty-five or more, fifty or more, and including 100 or more times per hour.

[0059] In other embodiments, the method includes applying a topical naloxone composition to the skin surface of a subject when treating or preventing an inflammatory skin condition that has been shown to be partially or completely resistant to treatment with other active agents (e.g., steroidal drug therapy, anti-inflammatory agents, or immunosuppressants). In these embodiments, the application of the topical naloxone composition described herein is sufficient to reduce the amount of steroid, anti-inflammatory agent, or immunosuppressant administered to the subject to treat the skin condition by, for example, 5% or more (by weight), 10% or more (by weight), 25% or more (by weight), 50% or more (by weight), 75% or more (by weight), 90% or more (by weight), and including 95% or more (by weight). In some embodiments, the application of the target topical naloxone composition and its continuous contact with the skin surface is sufficient to completely replace the treatment of the inflammatory skin condition with steroid, anti-inflammatory agent, or immunosuppressant.

[0060] In some cases, the method includes, while treating inflammatory skin conditions (e.g., atopic dermatitis, eczema, psoriasis), replacing one or more administrations of steroid therapy, anti-inflammatory agent, or immunosuppressant with the application of the topical naloxone composition described herein, for example, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 15 or more, 25 or more, 50 or more, 75 or more, and including 100 or more planned administrations of steroid therapy, anti-inflammatory agent, or immunosuppressant to treat the inflammatory skin condition. Therefore, applying and maintaining the topical naloxone composition described herein may be sufficient to reduce the number of planned steroid treatments, anti-inflammatory agents, or immunosuppressant administrations for the treatment of inflammatory skin conditions by 5% or more, for example, 10% or more, 15% or more, 20% or more, 25% or more, 50% or more, 75% or more, 90% or more, 95% or more, and including reducing the number of planned steroid treatments, anti-inflammatory agents, or immunosuppressant administrations for the treatment of inflammatory skin conditions by 99% or more.

[0061] In some embodiments, the target method is suitable for completely replacing steroid treatment, anti-inflammatory agent or immunosuppressant administration with the topical naloxone composition described herein in the treatment of inflammatory skin conditions.

[0062] In some embodiments, the method includes administering and maintaining one or more target topical naloxone compositions in combination with steroid treatment, anti-inflammatory agent, or immunosuppressant administration while treating an inflammatory skin condition. In some cases, when the topical naloxone composition comes into contact with the subject, the dose of the steroid, anti-inflammatory agent, or immunosuppressant administered to the subject to treat the inflammatory skin condition may be reduced. For example, the dose of each planned steroid, anti-inflammatory agent, or immunosuppressant administration may be reduced by 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 50% or more, and including 75% or more. In some cases, for steroids, anti-inflammatory agents, or immunosuppressants, one or more planned administrations may be canceled (i.e., skipped), for example, at intervals of one planned administration, two planned administrations, three planned administrations, four planned administrations, or other time intervals. In some cases, the application of one or more topical naloxone compositions is sufficient to cancel a scheduled administration of a steroid, anti-inflammatory agent, or immunosuppressant, such as two or more scheduled administrations, three or more scheduled administrations, and including four or more scheduled administrations of a steroid, anti-inflammatory agent, or immunosuppressant.

[0063] In some embodiments, the compositions of the present invention may be administered before, during, or after the administration of other therapeutic agents for treating the same or unrelated conditions. If provided concurrently with another therapeutic agent, the target topical naloxone composition may be administered with the same or different compositions. Thus, the target naloxone composition and other therapeutic agents may be administered to a subject in a concurrent therapeutic manner. "Concurrent therapeutic" means administration to a subject such that the combination of substances produces a therapeutic effect in the treated subject. For example, concurrent therapeutic can be achieved by co-administering the naloxone composition of the present invention with a pharmaceutical composition having at least one other agent, such as an anti-inflammatory agent, immunosuppressant, steroid, analgesic, anesthetic, antihypertensive agent, chemotherapeutic agent, etc., which, according to a specific dosing regimen, constitute a therapeutically effective dose. The administration of the individual pharmaceutical compositions may be simultaneous or at different times (i.e., sequentially, in any order, on the same day, or on different dates), provided that the combination of these substances produces a therapeutic effect in the treated subject.

[0064] When the naloxone composition and the second therapeutic agent are administered simultaneously to treat the same condition, the weight ratio of naloxone to the second therapeutic agent may range from 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 a corresponding range thereof. For example, the weight ratio of naloxone to the second therapeutic agent may range from 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 may range from 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 a range thereof. For example, the proportion of the second therapeutic agent naloxone may range from 1:1 to 5:1, 5:1 to 10:1, 10:1 to 15:1, or 15:1 to 25:1.

[0065] As described above, aspects of the invention include 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 includes maintaining continuous contact between the topical composition and the subject, sufficient to deliver a target dose of naloxone to the subject's local skin surface, for example, delivering a target dose determined based on total local drug exposure or average daily local drug exposure.

[0066] In some embodiments, the topical naloxone compositions are formulated such that, when applied to the skin surface of a subject, the compositions exhibit less transdermal water loss than naloxone compositions containing a hydrophobic delivery solvent (e.g., petrolatum). For example, the topical naloxone compositions described herein are formulated such that, when applied to the skin surface of a subject, the compositions exhibit less transdermal water loss than naloxone compositions containing a hydrophobic delivery solvent by 0.5 g / m². 2 / hr or more, for example, 1 g / m 2 / hr or more, 1.5 g / m 2 / hr or more, 2 g / m 2 / hr or more, 3 g / m 2 / hr or more, 5 g / m 2 / hr or more, 10 g / m 2 / hr or more, and includes 25 g / m 2 / hr or more. In some embodiments, the topical naloxone composition exhibited a transdermal water loss of 25 g / m² when applied to the skin surface of a subject. 2 / hr or less, for example, 20 g / m 2 / hr or less, 15 g / m 2 / hr or less, 10 g / m 2 / hr or less, and includes 5 g / m 2 / hr or less.

[0067] In some embodiments, the method may include maintaining continuous contact between the topical naloxone composition and the subject, sufficient to deliver a predetermined amount of naloxone to the subject. When the method includes delivering a predetermined amount of naloxone to the subject, the amount of naloxone delivered topically may range from 0.001 mg to 2 mg, for example, 0.005 to 1.9 mg, 0.01 mg to 1.8 mg, 0.05 to 1.7 mg, 0.1 mg to 1.6 mg, 0.5 mg to 1.5 mg, and includes 0.5 mg to 1 mg.

[0068] In some embodiments, the predetermined amount of naloxone delivered to the subject may be a percentage of the total amount of naloxone present in the topical composition. For example, the predetermined amount of naloxone delivered topically to the subject may be 1% or more of the total amount of naloxone present in the topical composition, such as 2% or more, 5% or more, 10% or more, 25% or more, and including 50% or more of the total amount of naloxone present in the topical composition. In other words, the method may include continuously contacting the naloxone composition with the subject such that an amount sufficient to topically deliver 5% or more of the naloxone in the topical composition to the subject within a single dosing interval. For example, in the case where the topical composition contains 1 mg of naloxone, the method may include continuously contacting the topical composition with the subject such that it is sufficient to locally deliver 0.05 mg or more of naloxone to the subject during dosing intervals, such as 0.1 mg or more, 0.25 mg or more, 0.4 mg or more, 0.45 mg or more, and including 0.5 mg or more of naloxone present in the topical composition.

[0069] In some embodiments, each of the target methods described below may further include the step of removing the topical composition from the subject's skin at the end of the dosing interval. For example, the topical composition may be removed from the subject's skin after the topical composition has been in continuous contact with the subject for 0.1 hours or longer (e.g., 0.5 hours or longer, 1 hour or longer, 2 hours or longer, 4 hours or longer, 6 hours or longer, 8 hours or longer, 12 hours or longer, 16 hours or longer, 20 hours or longer, and including 24 hours or longer).

[0070] As described above, a dosing interval refers to a single dosing process achieved by applying the topical composition and maintaining continuous contact with the subject, the interval beginning with the application of the topical composition to the subject's skin and ending when the topical composition is removed from the subject's skin or when all naloxone in the composition has been locally delivered to the subject. In some embodiments, the regimen may include multiple dosing intervals. When implementing the method of the present invention, the treatment regimen may include two or more dosing intervals, for example, three or more dosing intervals, four or more dosing intervals, five or more dosing intervals, including ten or more dosing intervals.

[0071] In some cases, subsequent dosing intervals in a treatment regimen may contain higher or lower concentrations of naloxone than those used in previous dosing intervals. For example, the naloxone concentration may be increased by 10% or more in subsequent dosing intervals, such as 20% or more, 50% or more, 75% or more, 90% or more, and including 100% or more. In some cases, the upper limit for the increase in naloxone concentration in subsequent dosing intervals is 10 times or less, such as 5 times or less, 2 times or less, 1 time or less, 0.5 times or less, and including 0.25 times or less.

[0072] On the other hand, the naloxone concentration may be reduced during subsequent dosing intervals, for example, by 10% or more, 20% or more, 50% or more, 75% or more, 90% or more, and including 100% or more. In some cases, the upper limit for the reduction in naloxone concentration during subsequent dosing intervals is 10 times or less, for example, 5 times or less, 2 times or less, 1 time or less, 0.5 times or less, and including 0.25 times or less.

[0073] As mentioned above, in other cases, subsequent dosing intervals may contain naloxone free base formulations that differ from previous dosing intervals, such as different types of polyethylene glycol and the amount of polyethylene glycol.

[0074] In some embodiments, the skin is evaluated to assess any changes in the skin to which the topical naloxone composition has been applied, such as determining the quality or color of the skin at the application site, and whether any damage, pain, swelling, or dryness has been reduced by continued contact of the topical naloxone composition with the subject. In some embodiments, the skin is evaluated to assess transdermal water loss through the skin.

[0075] The application site can be evaluated at any time during the implementation of the target method. In some cases, while the topical composition is in continuous contact with the subject, the skin is evaluated by observing or palpating the skin at fixed time intervals, such as every 0.25 hours, every 0.5 hours, every 1 hour, every 2 hours, every 4 hours, every 12 hours, every 24 hours, and every 72 hours or other time intervals. For example, while the topical composition is in continuous contact with the subject, the application site can be evaluated at times such as 15 minutes after application, 30 minutes after application, 1 hour after application, 2 hours after application, 4 hours after application, 8 hours after application, 12 hours after application, and including 24 hours after application.

[0076] In other embodiments, the application site of the topical composition should be evaluated after the topical composition has been removed from the subject's skin. For example, the application site may be evaluated 30 minutes after the removal of the topical composition, or 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and even 24 hours after the removal of the topical composition.

[0077] In some embodiments, the application site of the topical composition needs to be evaluated before administering the topical composition to the subject, for example, by recording skin color and texture before the start of the dosing interval. For example, the application site can be evaluated 5 minutes before applying the topical composition, or at 10, 30, 60, 120, 240 minutes, and including 480 minutes before application. If the method involves multiple sequential dosings, the application site can be evaluated after each removal of the topical composition from the skin and before the administration of a subsequent dose of the topical composition. For example, when removing the first topical composition, the application site can be evaluated at 2, 4, 6, 12, and 24 hours after removal and before the administration of the second topical composition. The subsequent topical composition can be applied to the previous application site immediately after the skin is evaluated, or it can be applied after a predetermined time following the evaluation of the skin, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after the skin is evaluated.

[0078] In some cases, the method includes assessing the severity of the treated condition after application of the topical composition, for example, to determine whether the composition is effective in treating the condition of the subject. Therefore, the method may include assessing the severity of a skin condition of the subject, 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, after application of the topical composition. For example, in some cases, the method includes assessing the severity of an inflammatory skin disease, such as atopic dermatitis, eczema, psoriasis, or a combination thereof. In other cases, the method includes assessing the severity of a non-inflammatory skin disease, such as chronic prurigo. In still other cases, the method includes assessing the severity of pruritus. In some cases, the pruritus is pruritus associated with one or more of the following: primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, neurological disorders, or pregnancy. In some embodiments, the pruritus is drug-induced pruritus or pruritus induced by pruritogens. In some embodiments, the pruritus is associated with a condition selected from herpes zoster, psoriasis, urticaria, paresthesia, Gover's disease, chronic kidney disease, and Hailey-Hailey disease. The pruritus may be accompanied by skin redness, bumps, plaques or blisters, dry or cracked skin, leathery skin, or scaly skin, and the method may further include administering a targeted naloxone composition in an amount sufficient to treat one or more of the following as accompanied by pruritus: skin redness, bumps, plaques or blisters, dry or cracked skin, leathery skin, or scaly skin.

[0079] Reagent test kit The present invention also provides kits for use in carrying out certain methods described herein. In some embodiments, the kit comprises one or more topical naloxone compositions, such as those described herein. In some embodiments, the kit includes a dispensing device, such as a dropper or metering dispenser. In some cases, the topical naloxone composition is contained in a squeeze tube, such as a squeeze tube configured to contain an ointment. The kit may also include an applicator, such as a sponge, brush, scraper, applicator, smoothing device, or a combination thereof. In some embodiments, the kit further includes a cover, such as a waterproof adhesive cover for covering the application site of the topical composition.

[0080] In a given kit comprising two or more target topical compositions, the compositions may be individually packaged or contained in the same container. In some embodiments, the kit will further include instructions for carrying out the target method or obtaining the method's pathway (e.g., a webpage providing instructions accessible to the user via a website URL), which may be printed on a substrate, wherein the substrate may be one or more of the following: instruction manual, packaging, reagent containers, etc. In the target kit, one or more components may be included in the same or different containers for convenience or as needed.

[0081] The following examples are for illustrative purposes only and are not intended to be limiting. experiment A. Degradation product detection The formulation preparation method, further detailed below, is as follows: First, all components except PEG1450 (e.g., low-MW PEG, NLX, and other additives such as antioxidants, glycerin, citric acid, etc.) are added at room temperature and stirred; then PEG1450 is added and heated to approximately 50°C until all PEG1450 has melted. After forming a homogeneous mixture, it is filled into tubes (one-inch laminated tubes from Albaa with a 0.305-inch orifice) and sealed with foil. The inner layer material of the laminated tube is linear low-density polyethylene (LLDPE). The filled tubes are cooled to room temperature to allow an opaque ointment to form inside.

[0082] Stability studies were conducted on PEG-based naloxone ointment formulations at 25°C, 40°C, and 60°C. Under all these temperature conditions, a specific degradation product (also known as a “related substance”) was consistently observed to form. This related substance typically appears within one week of formulation preparation. Using primarily HPLC, we found that the amount of degradation product relative to naloxone increased further with increasing temperature and humidity. We found that the content of this related substance was quite high, and it consistently formed with various excipients and under various storage conditions. Over time, it appears that a small fraction of naloxone chemically degrades via an oxidative process to produce the related substance (relative retention time (RRT) of 0.79 determined by HPLC). The impurity at RRT 0.79 is an unknown related substance.

[0083] We also found that naloxone hydrochloride is unstable in PEG-based formulations. A 9.1% aqueous solution of naloxone hydrochloride was prepared. 1.00 g of the 9.1% aqueous solution of naloxone hydrochloride was mixed with 4.70 g of PEG 300 and 4.30 g of PEG1450 to obtain a total weight of 10.00 g of 0.91% naloxone hydrochloride, thus preparing a PEG-based formulation. The stability of this naloxone hydrochloride formulation was evaluated by HPLC at room temperature over two months. As shown in Table 1 below, the increase in the number of degradation products was significantly increased in the second month. This indicates that naloxone hydrochloride is also unstable in this PEG-based formulation. Deg 1 matches the relative retention times of the aforementioned unknown related substances.

[0084] Table 1

[0085] B. Isolation and identification of naloxone N-oxide The separation of unknown related substances using multi-step liquid chromatography was time-consuming and labor-intensive due to the need to separate a large amount of PEG material to identify the target degradation products. Approximately 200 g of PEG300 containing 1% naloxone free base ointment was aged in a humidity chamber and used for the separation operation. A C18 column was washed with a 6.2 mM aqueous solution of sodium 1-octanesulfonate containing 0.1% phosphoric acid, followed by elution with 40% methanol to enrich the target degradation products in the formulation sample. The fractions containing the related substances were mixed and lyophilized. The degradation products were separated by preparative HPLC using a Shimadzu Prominence preparative HPLC system. A Phenomenex Luna C18 column (5 μm, 21.2 x 150 mm) equipped with a Security Guard PREP C18 column (21.2 x 15 mm) was used.

[0086] A 6.2 mM aqueous solution of sodium 1-octanesulfonate containing 35% methanol and 0.1% phosphoric acid was used. The flow rate was 20 mL / min for an isocratic run of 18 minutes. The UV detector wavelength was 205 nm. Fractions were collected between 7 and 14 minutes when a slope of 100 uV / sec and a voltage level of 50,000 uV were observed. Reanalysis of the fractions by analytical HPLC showed that the purity of the relevant substances in the fraction sample was >99% (Appendix A23). Analytical purity was obtained by running an Agilent Zorbax EclipseXDB-C18 (5 μm, 4.6 x 150 mm) column packed with a 6.2 mM aqueous solution of sodium 1-octanesulfonate containing 35% methanol and 0.1% phosphoric acid for 15 minutes. Final separation of impurities was completed using a strong cation exchange (SCX) column (washed with methanol and then eluted with 5% HCl aqueous solution) after buffer removal. The components containing the relevant substances were mixed, and the pH was adjusted to 7.0 ± 0.5. The degradation products were extracted four times with an equal volume of chloroform and isopropanol (3:1) mixture. The mixed organic extracts were dried over sodium sulfate and concentrated to a dry state. After purification by SCX column chromatography, the purity of the isolated degradation products was reduced to 92%.

[0087] After separating sufficient amounts of degradation products (in milligrams), they were characterized by mass spectrometry and NMR. High-resolution mass spectrometry data of the separated degradation products were acquired using a Waters UPLC Xevo G2-XS QT system controlled by Waters UNIFI software. A Waters CORTECS UPLC Shield RP18 (1.6 μm 3 x 50 mm) column was used. Mobile phase A was 0.1% aqueous formic acid, and mobile phase B was 0.1% formic acid acetonitrile. The flow rate was 0.2 mL / min. A gradient of B from 5% to 90% was used over 5 minutes. The molecular formula given by HRMS was C19H21NO5, with a mass error of less than 5 ppm.

[0088] NMR data were acquired at ambient temperature using a Bruker 400 MHz spectrometer. Chemical shifts (in ppm) are reported relative to TMS. (Using nuclear...) 1 H, 13 C and 15 N was used in NMR experiments, including two-dimensional NMR experiments. The signals observed in the obtained 1H NMR spectra were consistent with the expected proton number and proton type of the proposed structure. 13Analysis of the 19 C NMR spectra revealed 18 resonance states for the 19 carbon atoms. Carbon atom assignment was performed using available data from all NMR experiments. 15 The NMR spectrum shows a single resonance state of a nitrogen atom at 129.2 ppm. The observed... 15 The N-shift supports the designation of the proposed structure as an N-oxide. NMR data confirmed that the naloxone core structure was intact, with no proton or carbon atom signal loss. Importantly, 21 protons, 5 CH carbon atoms, and 7 CH2 carbon atoms were observed, indicating that the additional oxygen atom identified by mass spectrometry was not bonded to any carbon atom. A significant low-field shift was observed for the two exchangeable protons and the signals assigned to H9, H16, H17, and H10 compared to naloxone. Nitrogen atom NMR results showed a significant shift from 41.5 ppm (naloxone) to 129.2 ppm (degradation product). These data indicate a significant change in the electronic structure around the nitrogen atom for the impurity. MS data concluded that the impurity was naloxone N-oxide. Finally, the separated relevant substances were directly compared with commercially available naloxone N-oxide standards by HPLC. The amount of naloxone N-oxide was first determined using naloxone standards and then corrected according to the response factor. The response factor for naloxone N-oxide is 1.19.

[0089] Comparison of naloxone structure and naloxone N-oxide structure:

[0090] C. Forced Degradation Study of Naloxone Forced degradation studies were conducted on 0.5% naloxone active pharmaceutical ingredient (Siegfried, batch 1530F001) in the presence of 5N hydrochloric acid, 5N sodium hydroxide, or 3% hydrogen peroxide (for 18 hours) or at 60°C (for 2 weeks) as controls. Except for hydrogen peroxide treatment, the peak area of ​​total related substances detected in the control and other treatment groups was less than 1% of the total area. Conversely, 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 RRT corresponded to the related substance peak at 0.79 RRT and was identified as naloxone N-oxide. The peak at 0.94 RRT co-eluted with the naloxone peak. Compared to other stressors, this forced degradation clearly demonstrates the reactivity of naloxone with peroxides and its degradation potential due to oxidation.

[0091] D. Summary of attempts to stabilize PEG-based naloxone ointments A major problem encountered in the formulation development of PEG-based naloxone ointments is the chemical instability caused by the interaction between naloxone and PEG due to oxidation. Several different approaches have been investigated to address this stability issue, including: ● Use antioxidants (citric acid, BHT, tocopherol, and sodium metabisulfite) ● Manufacturing, processing, and storage are controlled using inert gases (argon or nitrogen). ● Use different PEGs (PEG 300 and PEG 400) ● Use PEG from different sources (PEG from Dow, Croda, BASF, EMD Millipore and Clariant) In summary, the formulation with optimal stability can be obtained through the following basic methods: 1. Use Croda super refined PEG 400 in an unopened container. 2. Implement argon protection during the mixing process. 3. Before filling, blow argon bubbles through the melted ointment. 4. Use an argon gas covering layer in the top space of the tube or container to prevent the ointment from coming into contact with air. 1. Formulations containing antioxidants The formulation was prepared as follows: all components except PEG1450 were added and stirred at room temperature; then PEG1450 was added and heated to approximately 50°C until all PEG1450 melted. After forming a homogeneous mixture, it was filled into tubes and capped, then allowed to cool to room temperature to form an opaque ointment. Tocopherol and / or citric acid were added as antioxidants to 1% PEG-based naloxone (NLX) ointment. The difference in stability between PEG 300 and PEG 400 after 3 months at 25°C was investigated, and the results are shown in Table 2 below.

[0092] Table 2

[0093] Although some differences were observed between different formulations, neither the addition of antioxidants nor changes in the PEG used brought the ointment to a stable state that reduced naloxone N-oxide to a sufficiently low (near-zero) level. Additional studies were conducted on other formulations at shorter time points, and the results are shown in Table 3 below.

[0094] Table 3

[0095] Similarly, the added antioxidants do not sufficiently stabilize naloxone in the ointment to a level where naloxone N-oxide is close to zero.

[0096] 2. Use low molecular weight PEG with extremely low peroxide value. 1% (w / w) naloxone base ointments were prepared using PEG300 or PEG400 from different sources (Dow, Croda, BASF, EMD Millipore, and Clariant). The initial peroxide value of the low molecular weight PEG used in the different PEG sources and the naloxone stability as reflected by the growth of naloxone N-oxide degradation products were investigated. These ointments were prepared using the following basic procedure: 1. Use PEG 300 or PEG 400 in an unopened container. 2. Implement argon protection during the mixing process. 3. Before filling, blow argon bubbles through the melted ointment. 4. Use an argon gas covering layer in the top space of the tube or container to prevent the ointment from coming into contact with air. The following 1% naloxone ointment was prepared, and the results are summarized in Table 4 below: Table 4

[0097] Figures 1 and 2 show the percentage of naloxone N-oxide in all these ointments. Ointments prepared with PEG 300 or PEG 400 containing 12 ppm or less peroxide have naloxone N-oxide at negligible and pharmaceutically acceptable levels, while ointments prepared with low molecular weight PEG with higher levels of peroxide, even purified PEG 400 obtained from Dow, show unacceptable growth of this identified degradation product over time.

[0098] Table 5 below presents stability data for a 1% naltrexone (w / w) formulation prepared using Croda super-refined PEG 400 (1% API, 60% PEG 400, 39% PEG 1450). A response factor of 1.19 was used to calculate the levels of the degradation product naloxone N-oxide. For other unknown related substances, a response factor of 1 was assumed. These data in the table below indicate that, for the purposes of these assays, the stability data are based on 6 months and 40 days. o According to data at C / 75% RH, the formulation prepared using PEG400 with low peroxide content and the aforementioned method exhibits acceptable stability during 2 years of storage at room temperature.

[0099] Table 5

[0100] 3. Minimum impact of argon gas during processing and storage 1.0% PEG-based naloxone free base (NLX) ointments were prepared using Croda super-refined (low peroxide content) PEG 400 (60%) and PEG1450 (39%), with or without argon blowing through the melted ointment, and the ointment tubes were covered with a capping layer. Alternatively, the same formulation was prepared using PEG 400 with a not low peroxide content and with an added argon treatment process. In a 6-month accelerated stability study at 40°C / 75% RH, the PEG 400 (SR) formulation with and without argon treatment showed low concentrations of degradation product 1 (naloxone N-oxide), while the PEG 400 formulation with a higher peroxide content showed higher concentrations of this degradation product (see Table 6 below). Note that for the PEG 400 (Hi) formulation with a higher peroxide content, this result was actually partially masked over a longer period by the further degradation of naloxone N-oxide into other degradation products. Argon treatment did not significantly improve the degradation rate, while the peroxide level in PEG 400 had a profound impact.

[0101] Table 6

[0102] E. Identification of other impurities 1. Gradient determination method In the HPLC method used in previous studies (the "old" method), another impurity was suspected to co-elute with N-oxides. A new gradient assay with a longer run time was developed to quantify this potential new impurity. Furthermore, in the "old" method, the sample concentration was 100 µg / mL, which resulted in higher limits of quantitation (LOQ) and detection (LOD). The "new" method, by increasing the sample concentration to 500 µg / mL, achieves higher sensitivity. The "new" impurity assay has an LOQ of approximately 0.03% and an LOD of 0.02%. The "old" impurity assay was also used as a control. The "new" method is used in the following examples.

[0103] Table 7 Comparison of "old" and "new" methods for determining impurities

[0104] Table 8 Flow gradient in new impurity determination method

[0105] 2. The effect of high molecular weight PEG A 1.0% PEG-based naloxone free base (NLX) ointment was prepared using Croda super-refined (low peroxide content) PEG 400 (60%) and PEG1450 (39%) from two different manufacturers (Dow and BASF). Both ointments underwent argon purging during preparation. Table 9 clearly shows that Dow PEG1450 consistently exhibited higher levels of impurity growth at all five RRTs, especially when stored at 40°C. In other words, the formulation prepared using BASF PEG1450 and Croda PEG 400 was more stable.

[0106] Table 9 Stability data of selected impurities used for comparison of BASF and Dow PEG1450

[0107] 3. Effects of antioxidants on formulations prepared using BASF PEG1450 This more stable formulation (i.e., the formulation prepared from BASF PEG1450 and Croda PEG 400) is also prepared by adding selected antioxidants BHT and propyl gallate, both of which are soluble in polyethylene glycol.

[0108] The following changes were made to this set of experiments. First, storage at 60°C was replaced with storage at 40°C. 40°C is not a typical accelerated stability condition for this PEG ointment because below 40°C the composition may contain both liquid and solid components, while at 40°C the ointment is in a liquid state; that is, a phase transition to liquid occurs, and 40°C represents a more extreme challenge to stability than just a temperature shift. Storage at 60°C is similar to forced degradation conditions and can be considered the worst-case scenario. At 60°C, the ointment is completely liquid. One month at 60°C is equivalent to two years at 25°C. Because such extreme temperatures may allow for different degradation pathways, some degradation that may occur at 60°C may never occur at lower temperatures. Second, in this study, the results are reported as a percentage (%) of the total ointment volume. The target API loading was 1%.

[0109] Although antioxidants have been used in formulations prepared with Dow PEG in the past, the impurity concentration in Dow PEG formulations was too high for the effect of antioxidants to be observed. The overall impurity levels in formulations prepared with Croda super-refined PEG 400 and BASF PEG 1450 are significantly lower than in previous formulations. In this case, the use of a selected antioxidant appears to be beneficial for formulations prepared with Croda PEG 400 and BASF PEG 1450. Tables 10 and 11 compare formulations prepared with and without antioxidants, 1% propyl gallate, and 0.1% BHT using Croda PEG 400 and BASF PEG 1450. Batch 209-132-1 is similar to batch 209-115-1 in Table 9, except that it contains BASF PEG 1450. Specifically, we found that the formulations containing 0.1% BHT in Table 10 had no impurity content higher than 0.2% after being stored at 60°C for one month, while the formulations containing 1% propyl gallate were more stable than the same formulations without antioxidants.

[0110] Table 10 Stability data for selected impurities in BASF formulations and antioxidants

[0111] Note: 1. For impurities, the quantity is expressed as % API; for assay values, the quantity is expressed as % API loading. 2. “----” means “not detected”.

[0112] Storage at 30°C was also used as a milder acceleration condition, in which there was no phase transition to liquid. Even after 3 months of storage at 30°C, the same trend was observed: formulations without antioxidants were less stable, formulations containing propyl gallate were more stable, and formulations containing BHT were the most stable.

[0113] Table 11 Stability data for selected impurities of the same BASF formulation and antioxidant.

[0114] To determine the effect of BHT concentration on the stability of naloxone in Croda PEG 400 / BASF PEG 1450, a stability study was conducted at 40 °C. The results showed that stability was improved even at 0.02% BHT.

[0115] Table 12 Stability data of selected impurities at 40°C for BASF PEG 1450 formulations containing different concentrations of BHT.

[0116] We also investigated a third source, JP Macrogol 1500R (Table 6), which has a molecular weight close to that of PEG1450. The results showed that the stability was improved when it contained antioxidants, and it was better than Dow PEG1450, but not as good as BASF PEG1450.

[0117] Table 13 Stability data of selected impurities in JP Macrogol 1500R formulation at 40°C

[0118] The table below shows other examples of the effects of antioxidants, confirming the improved results in the presence of BHT and propyl gallate, and also demonstrating that propyl gallate (even at 0.1% propyl gallate) can indeed improve stability. Data collected on this Croda PEG 400 / BASF PEG 1450, comparing the presence of 0.05% propyl gallate with 0.1% BHT, showed that after 3 months at 60°C, the impurity levels at RRT0.81 were 0.05 and 0.06, respectively. The use of propyl gallate at concentrations as low as 0.05% or 0.02% BHT with BASF PEG 1450 can improve the stability of the ointment.

[0119] Table 14 Data on BASF PEG1450 containing antioxidants at 60°C

[0120] Table 15

[0121] F. Efficacy of naloxone ointment in a rat model of atopic dermatitis and pruritus Atopic dermatitis skin symptoms were induced in mice (HOS:HR-1 hairless) by providing them with a special diet. Starting on day 34, each mouse in all groups was treated with an ointment at a dose of 0.1 ml / day on the entire back once daily for three weeks. Mice were video-recorded for 30 minutes before administration (baseline activity) on days 34, 35, 38, 41, 45, 48, and 55, and scratching was observed within one hour after administration. The topical naloxone active ingredient composition was allowed to dry for 15–(1) hours before video recording of scratching behavior. Scratching behavior was monitored every 5 minutes for 1 hour, with the scratch count including the count of one or more of the following actions: raising the hind legs, scratching the back, or lowering the legs to the floor. The cumulative duration of scratching behavior was also determined. Transdermal water loss (TEWL) was also measured on days 34, 48, 55, and 20 (phase 2) and days 33 and 55 (phase 3). Information on the therapeutic formulations by group is shown in Table 16 below.

[0122] Table 16

[0123] Figure 3 depicts the mean number of scratches and cumulative scratching duration exhibited by mice administered the following treatments on days 34 and 41, and Figure 4 depicts the mean number of scratches and cumulative scratching duration exhibited by mice administered the following treatments on days 48 and 55: 1) placebo (without naloxone active agent); 5 or 2) topical composition containing naloxone free base. Results also compared scratching behavior in mice administered topical compositions with a hydrophilic delivery solvent (containing polyethylene glycol) or a hydrophobic delivery solvent (petrolatum).

[0124] Figure 5 depicts the mean number of scratches and cumulative scratching duration exhibited by mice administered the following treatments on days 34 and 41, and Figure 6 depicts the mean number of scratches and cumulative scratching duration exhibited by mice administered the following treatments on days 48 and 55: 1) placebo (without naloxone active agent); or 2) topical composition containing naloxone hydrochloride. Results also compared scratching behavior in mice administered topical compositions with a hydrophilic delivery solvent (containing polyethylene glycol) or a hydrophobic delivery solvent (petrolatum).

[0125] As shown in Figure 3-6, the average number of scratches and the cumulative scratching duration were reduced after topical delivery of naloxone free base or naloxone hydrochloride. Furthermore, the average number of scratches and the cumulative scratching duration were significantly reduced after application of a topical composition containing naloxone active agent and a hydrophilic delivery solvent (polyethylene glycol).

[0126] Figures 7A-7C depict the transdermal water loss observed on days 34, 48, and 55 in the placebo (without naloxone active agent) and topical compositions containing naloxone free base. As shown in Figures 7A-7C, the compositions containing hydrophobic delivery solvents exhibited greater transdermal water loss, which is abnormal, as hydrophobic delivery solvents (e.g., petrolatum) typically reduce water loss.

[0127] Figures 8A-8B depict the transdermal water loss observed on days 33 and 55 in the placebo (without naloxone active agent) and topical compositions containing naloxone hydrochloride. As with compositions containing the free base of naloxone, compositions containing a hydrophobic delivery solvent exhibited greater transdermal water loss than compositions containing only polyethylene glycol as a hydrophilic delivery solvent.

[0128] Figures 9A-9B depict example photographs of mouse skin after administration of a placebo (without naloxone active agent) composition and a topical composition having naloxone free base and a hydrophobic delivery solvent. Figures 10A-10B depict example photographs of mouse skin after administration of a placebo (without naloxone active agent) composition and a topical composition having naloxone hydrochloride and a hydrophilic delivery solvent containing only polyethylene glycol. Figures 9A-9B The comparison with Figures 10A-10B shows that mouse subjects who were given a topical composition consisting only of a hydrophilic delivery solvent experienced less skin irritation, redness, and damage due to scratching.

[0129] All tested topical naloxone compositions demonstrated antipruritic effects in a 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 hydrochloride + PEG (days 34 and 55) and naloxone hydrochloride + Shea XP (days 34, 41, 48, and 55) significantly reduced scratching behavior. However, the formulations containing Shea XP showed significantly higher transdermal water loss compared to PEG formulations containing either naloxone base or naloxone hydrochloride.

[0130] In at least some of the foregoing embodiments, one or more elements used in one embodiment may be used interchangeably in another embodiment, unless such substitution is technically impractical. Those skilled in the art will understand that various other omissions, additions, and modifications may be made to the methods and structures described above without departing from the claimed subject matter. All such modifications and alterations are intended to be covered by the scope of the subject matter as defined in the appended claims.

[0131] Those skilled in the art will understand that, in general, the terms used herein, and particularly those used in the appended claims (e.g., in the body of the appended claims), should generally be understood as “open-ended” terms (e.g., the term “comprising” should be interpreted as “including but not limited to,” and the term “having” should be interpreted as “at least having,” etc.). Those skilled in the art will also understand that if it is intended to specify a specific number in the introduced claim, such intention will be expressly indicated in the claim, and the absence of such express indication is not considered to indicate the absence of such intention. For example, to aid understanding, the appended claims may use the introductory phrases “at least one” and “one or more” to introduce a feature in the claim. However, the use of such phrases should not be construed as implying that a claim feature introduced by the indefinite article "a" or "an" limits any particular claim containing that feature to an embodiment containing only one of that feature, even if the claim includes both the introductory phrase "one or more" or "at least one" and the indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be interpreted as meaning "at least one" or "one or more"); the same applies when using definite articles to introduce features in a claim. Furthermore, even when a specific number of claim features is explicitly stated, those skilled in the art should recognize that such enumeration should be interpreted as meaning at least the number listed (e.g., the phrase "two features" without other modifiers means at least two of that feature, or two or more of that feature). Furthermore, when using expressions such as "at least one of A, B, and C," the expression should generally be interpreted in accordance with the meaning commonly understood by a person skilled in the art (e.g., "a system having at least one of A, B, and C" should include, but is not limited to, systems having A alone, having B alone, having C alone, having A and B, having A and C, having B and C, and / or having A, B, and C, etc.). When using expressions such as "at least one of A, B, or C," the expression should generally be interpreted in accordance with the meaning commonly understood by a person skilled in the art (e.g., "a system having at least one of A, B, or C" should include, but is not limited to, systems having A alone, having B alone, having C alone, having A and B, having A and C, having B and C, and / or having A, B, and C, etc.). Those skilled in the art should also understand that any conjunction and / or phrase that substantially arbitrarily indicates two or more optional items, whether in the specification, claims, or drawings, should be understood to indicate the possibility of including one of these items, any one of these items, or both of these items. For example, the phrase “A or B” should be understood to include the possibility of “A” or “B” or “A and B”.

[0132] Furthermore, when features or aspects of the invention are described in the Markush group, those skilled in the art will recognize that the invention is therefore also described in the context of any single member or subgroup of members within that Markush group.

[0133] Those skilled in the art will understand that, for any and all purposes, such as for the purpose of providing written description, all ranges disclosed herein also include any and all possible subranges and combinations thereof. Any range listed herein can be readily regarded as sufficiently descriptive and implementing at least bisection, trisection, quartic division, quintic division, decimal division, etc. As a non-limiting example, each range discussed herein can be readily divided into a lower third, middle third, and upper third, etc. Those skilled in the art will understand that all language such as “up to,” “at least,” “greater than,” and “less than” includes the listed numbers and refers to ranges that can subsequently be divided into subranges as described above. Finally, those skilled in the art will understand that a range includes each individual number. Thus, for example, a group having 1-3 units means a group having 1, 2, or 3 units. Similarly, a group having 1-5 units means a group having 1, 2, 3, 4, or 5 units, and so on.

[0134] Although the invention has been described in detail with illustrations and examples for the purpose of clarity, it will be apparent to those skilled in the art, given the edifying significance of the invention, that certain changes and modifications may be made without departing from the spirit or scope of the appended claims.

[0135] Therefore, the foregoing only illustrates the principles of the invention. It should be understood that those skilled in the art can design various structures, although not explicitly stated or shown herein, but these designs reflect the principles of the invention and do not depart from its spirit and scope. Furthermore, all examples and conditional language listed herein are primarily intended to help the reader understand the principles of the invention and the inventors' ideas for further expanding the field, and should be interpreted as not being limited by these specifically listed examples and conditions. Moreover, all statements herein referencing the principles, aspects, and embodiments of the invention and their specific examples are intended to cover their structural and functional equivalents. Furthermore, the equivalents are intended to include currently known equivalents and those to be developed in the future, i.e., any functionally identical elements developed regardless of their structure. Moreover, no part of the invention will be disclosed to the public, whether or not it is explicitly stated in the claims.

[0136] Therefore, the scope of the invention is not limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the invention are embodied in the appended claims. In the claims, 35 U.S.C. 112(f) or 35 U.S.C. 112(6) is expressly invoked only when the limiting phrase “means for…” or “steps for…” is explicitly used at the beginning of the limiting phrase of the claims; if such phrase is not used in the limiting phrase of the claims, then 35 U.S.C. 112(f) or 35 U.S.C. 112(6) is not invoked.

Claims

1. A storage-stable non-aqueous topical composition comprising a naloxone free base and a non-aqueous solvent, wherein the composition is substantially free of naloxone N-oxide.

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

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

4. The storage-stable non-aqueous topical composition according to any one of the preceding claims, wherein the non-aqueous solvent comprises a polyethylene glycol component.

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

6. The storage-stable non-aqueous topical composition according to 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 a corresponding average molecular weight higher than that of the first polyethylene glycol.

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

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

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

11. The storage-stable non-aqueous topical composition of claim 10, wherein the composition comprises 30% to 70% (by weight) of the first polyethylene glycol.

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

13. The storage-stable non-aqueous topical composition of claim 12, wherein the composition comprises 30% to 45% (by weight) of the second polyethylene glycol.

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

15. A storage-stable non-aqueous topical composition according to any one of the preceding claims, wherein the composition comprises: 1% (by weight) of naloxone free base, 50% to 70% (by weight) of a first polyethylene glycol (average molecular weight of 300 to 400 g / mol) and 30% to 45% (by weight) of a second polyethylene glycol (average molecular weight of 1450 g / ml).

16. A storage-stable non-aqueous topical composition according to any one of the preceding claims, wherein the composition is substantially free of one or more other impurities.

17. The storage-stable non-aqueous topical composition of claim 16, wherein one or more other impurities are selected from the group consisting of: RRT0.32, RRT0.43, RRT0.82, RRT0.86, and RRT2.

63.

18. A storage-stable non-aqueous topical composition according to any one of the preceding claims, wherein the composition comprises one or more antioxidants.

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

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

21. A storage-stable, non-aqueous topical composition according to any one of the preceding claims, wherein the composition is formulated to locally deliver the naloxone free base.

22. A storage-stable, non-aqueous topical composition according to any one of the preceding claims, wherein the composition is formulated to deliver the naloxone free base topically 2 to 7 hours after application.

23. A storage-stable non-aqueous topical composition according to any one of the preceding claims, wherein the composition is a cream, gel, lotion, or ointment.

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

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

26. The method of claim 25, wherein the method comprises treating or preventing inflammatory skin diseases.

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. The method of claim 25, wherein the method comprises treating or preventing non-inflammatory skin diseases.

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

30. The method of claim 25, wherein the method comprises treating or preventing pruritus.

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

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

33. The method according to any one of claims 25 to 32, wherein the composition is formulated to treat or prevent pruritus associated with skin conditions.

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

35. The method of claim 34, wherein the topical composition is applied to the subject's skin in a manner sufficient to cover the entire area of ​​the skin lesion.

36. The method according to any one of claims 25 to 35, wherein the topical composition is in continuous contact with the skin of the subject for 1 hour or longer.

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

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

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

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

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

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 a corresponding average molecular weight higher than that of the first polyethylene glycol.

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

44. The method of claim 43, wherein the average molecular weight of the first polyethylene glycol is 600 g / mol or lower, and the average molecular weight of the second polyethylene glycol is 1350 g / mol or higher.

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

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

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

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

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

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

51. The method according to 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 (average molecular weight of 300 to 400 g / mol) and 30% to 45% (by weight) of a second polyethylene glycol (average molecular weight of 1450 g / ml).

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

53. The method of claim 52, wherein the one or more other impurities are selected from the group consisting of: RRT0.32, RRT0.43, RRT0.82, RRT0.86, and RRT2.

63.

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

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

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

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

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

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

61. A reagent kit comprising: The external composition according to any one of claims 1-24; and Dispensing device.

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

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

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