Topical naloxone compositions and methods for using same

Abstract

To provide topical naloxone compositions for locally delivering naloxone to the skin of a subject.SOLUTION: Topical compositions according to certain embodiments are storage-stable non-aqueous topical compositions that include naloxone free base and a non-aqueous vehicle, where the compositions are substantially free of naloxone N-oxide. Also provided are methods of using the topical compositions to locally deliver naloxone to a subject, and kits containing the topical naloxone compositions.SELECTED DRAWING: None

Description

[Background technology]

[0001] Naloxone is an analgesic with high affinity for the μ-opioid receptor in the central nervous system. It is a medicinal μ-opioid receptor (MOR) antagonist. It has affinity for kephalin and β-endorphin, but not for dynorphin. The three most common types of μ-opioid receptors are Characterized mutants typically express presynaptic (e.g., peritubular gray regions and These are μ1, μ2, and μ3, which are found either at the synapse (neuronal dorsal horn and superficial dorsal horn) or postsynaptically.

[0002] Activation of μ-opioid receptors (e.g., by agonists) produces analgesia, sedation, and hypotension. May lead to decreased appetite, itching, nausea, euphoria, decreased breathing and meiosis. Opioid receptors can also be found in the intestinal tract, and activation of these receptors sometimes leads to peristalsis. Naloxone is commercially available as Narcan® Also known as Evzio® or Evzio®, it blocks the κ-opioid receptor and It has lower affinity at the δ-opioid receptor.

[0003] Naloxone is typically administered parenterally, such as by intravenous injection or infusion. This route of administration provides rapid delivery and complete bioavailability of the drug, and therefore Solution formulations for parenteral administration are inherently particulate-free. They must contain 100% ethanol and be sterile. It must be physically and chemically stable so that its properties are predictable. Summary of the Invention

[0004] An aspect of the present invention is a topical naloxone formulation for localized delivery of naloxone to the skin of a subject. The topical composition according to certain embodiments comprises naloxone free base and non- A storage-stable, non-aqueous topical composition comprising an aqueous vehicle and naloxone N-oxide. The topical composition is substantially free of naloxone. Methods, as well as kits containing topical naloxone compositions, are also provided. [Brief explanation of the drawings]

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

[0006] Aspects of the present invention include topical naloxone compositions for topically delivering naloxone to the skin of a subject. The topical compositions, according to certain embodiments, are storage-stable, non-aqueous topical compositions comprising naloxone free base and a non-aqueous vehicle, and are substantially free of naloxone N-oxide. Methods for topically delivering naloxone to a subject using the topical compositions are also provided, as well as kits comprising the topical naloxone compositions. Aspects of the present invention also include the following. Aspect 1 naloxone free base and a non-aqueous vehicle, Substantially free of naloxone N-oxide, A storage-stable non-aqueous topical composition. Aspect 2 2. The storage-stable non-aqueous topical composition of aspect 1, wherein the naloxone free base is present in the composition in an amount ranging from 0.05 to 10% by weight. Aspect 3 3. The storage-stable non-aqueous topical composition of aspect 2, wherein the naloxone free base is present in the composition in an amount ranging from 0.1 to 5% by weight. Aspect 4 Aspect 4. The storage-stable non-aqueous topical composition of any one of aspects 1-3, wherein the non-aqueous vehicle comprises a polyethylene glycol component. Aspect 5 5. The storage-stable non-aqueous topical composition of embodiment 4, wherein the polyethylene glycol component comprises two or more different polyethylene glycols of different average molecular weights. Aspect 6 6. The storage-stable non-aqueous topical composition of embodiment 5, wherein the polyethylene glycol component comprises a first polyethylene glycol having an average molecular weight of 1000 g / mol or less and a second polyethylene glycol having an average molecular weight higher than the first polyethylene glycol. Aspect 7 7. The storage-stable non-aqueous topical composition of embodiment 6, wherein the second polyethylene glycol has an average molecular weight of 1000 g / mol or greater. Aspect 8 8. The storage-stable non-aqueous topical composition of embodiment 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. Aspect 9 9. The storage-stable non-aqueous topical composition of embodiment 8, wherein the first polyethylene glycol has an average molecular weight of 300 to 400 g / mol. Aspect 10 10. The storage-stable non-aqueous topical composition of embodiment 9, wherein the second polyethylene glycol has an average molecular weight of 1400 to 1500 g / mol. Aspect 11 11. The storage-stable non-aqueous topical composition of aspect 10, comprising 30-70% by weight of the first polyethylene glycol. Aspect 12 11. The storage-stable non-aqueous topical composition of embodiment 10, comprising more of the first polyethylene glycol than the second polyethylene glycol. Aspect 13 13. The storage-stable non-aqueous topical composition of embodiment 12, comprising 30-45% by weight of the second polyethylene glycol. Aspect 14 Aspect 14. The storage-stable non-aqueous topical composition of any of aspects 6-13, wherein, as prepared, at least the first polyethylene glycol component contains 20 ppm or less of peroxide. Aspect 15 15. The storage-stable non-aqueous topical composition of any of the preceding aspects, comprising 1 wt. % naloxone free base, 50-70 wt. % of a first polyethylene glycol having an average molecular weight of 300-400 g / mol, and 30-45 wt. % of a second polyethylene glycol having an average molecular weight of 1450 g / ml. Aspect 16 16. The storage-stable, non-aqueous topical composition of any of embodiments 1-15, wherein the composition is substantially free of one or more additional impurities. Aspect 17 17. The storage-stable non-aqueous topical composition of embodiment 16, wherein the one or more additional impurities are selected from the group consisting of RRT 0.32, RRT 0.43, RRT 0.82, RRT 0.86, and RRT 2.63. Aspect 18 18. The storage-stable non-aqueous topical composition of any of embodiments 1-17, comprising one or more antioxidants. Aspect 19 19. The storage-stable non-aqueous topical composition of embodiment 18, wherein the one or more antioxidants are present in an amount ranging from 0.01 to 5.0% w / w. Aspect 20 20. The storage-stable, non-aqueous topical composition of aspect 18 or 19, wherein the one or more antioxidants are selected from the group consisting of BHT and propyl gallate. Aspect 21 21. The storage-stable, non-aqueous topical composition of any of aspects 1-20, formulated to deliver the naloxone free base locally. Aspect 22 22. The storage-stable, non-aqueous topical composition of any of aspects 1-21, formulated to deliver the naloxone free base locally for 2 to 7 hours after application. Aspect 23 23. The storage-stable non-aqueous topical composition of any of aspects 1-22, wherein the composition is a cream, gel, lotion, or ointment. Aspect 24 24. The storage-stable non-aqueous topical composition of embodiment 23, wherein the composition is an ointment. Aspect 25 applying to the skin of a subject a storage-stable, non-aqueous topical composition comprising naloxone free base and a non-aqueous vehicle; the composition is substantially free of naloxone N-oxide; method. Aspect 26 26. The method of embodiment 25, comprising treating or preventing an inflammatory skin disease. Aspect 27 27. The method of embodiment 26, wherein the inflammatory skin disease is selected from the group consisting of atopic dermatitis, eczema, psoriasis, and combinations thereof. Aspect 28 26. The method of embodiment 25, comprising treating or preventing a non-inflammatory skin disease. Aspect 29 29. The method of claim 28, wherein the non-inflammatory skin disease is chronic prurigo. Aspect 30 26. The method of embodiment 25, comprising treating or preventing pruritus. Aspect 31 31. The method of embodiment 30, wherein said pruritus is associated with one or more of an inflammatory skin disease, a non-inflammatory skin disease, primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, a neurological condition, or pregnancy. Aspect 32 The method of aspect 31, wherein the pruritus is drug-induced pruritus or pruritogen-induced pruritus. Aspect 33 Aspect 33. The method of any one of aspects 25-32, wherein the composition is formulated to treat or prevent itching associated with a skin condition. Aspect 34 34. The method of any one of aspects 25-33, wherein the topical composition is applied directly to the site of the skin condition. Aspect 35 35. The method of embodiment 34, wherein the topical composition is applied to the skin of the subject in a manner sufficient to cover the entire skin condition. Aspect 36 36. The method of any one of aspects 25-35, wherein the topical composition is maintained in contact with the skin of the subject for one hour or more. Aspect 37 37. The method of any one of aspects 25-36, wherein the topical composition is maintained in contact with the skin of the subject for 2 to 7 hours. Aspect 38 38. The method of any one of aspects 25-37, wherein the naloxone free base is present in the composition in an amount ranging from 0.05 to 10% by weight. Aspect 39 39. The method of claim 38, wherein the naloxone free base is present in the composition in an amount ranging from 0.1 to 5% by weight. Aspect 40 Aspect 40. The method of any one of aspects 25-39, wherein the non-aqueous vehicle comprises a polyethylene glycol component. Aspect 41 41. The method of embodiment 40, wherein the polyethylene glycol component comprises two or more different polyethylene glycols of different average molecular weights. Aspect 42 42. The method of embodiment 41, wherein the polyethylene glycol component comprises a first polyethylene glycol having an average molecular weight less than or equal to 1000 g / mol and a second polyethylene glycol having a higher average molecular weight than the first polyethylene glycol. Aspect 43 43. The method of embodiment 42, wherein the second polyethylene glycol has an average molecular weight of 1000 g / mol or greater. Aspect 44 44. The method of embodiment 43, wherein the first polyethylene glycol has an average molecular weight of 600 g / mol or less, and the second polyethylene glycol has an average molecular weight of 1350 g / mol or more. Aspect 45 45. The method of claim 44, wherein the first polyethylene glycol has an average molecular weight of 300 to 400 g / mol. Aspect 46 46. The method of claim 45, wherein the second polyethylene glycol has an average molecular weight of 1400 to 1500 g / mol. Aspect 47 47. The method of claim 46, wherein the composition comprises 30 to 70% by weight of the first polyethylene glycol. Aspect 48 48. The method of embodiment 47, wherein the composition comprises more of the first polyethylene glycol than the second polyethylene glycol. Aspect 49 49. The method of claim 48, wherein the composition comprises 30 to 45% by weight of the second polyethylene glycol. Aspect 50 Aspect 49. The method of any one of aspects 42 to 49, wherein at least the first polyethylene glycol component contains 20 ppm or less of peroxide at the time the composition is prepared. Aspect 51 51. The method of any one of aspects 25-50, wherein the composition comprises 1 wt. % naloxone free base, 50-70 wt. % of a first polyethylene glycol having an average molecular weight of 300-400 g / mol, and 30-45 wt. % of a second polyethylene glycol having an average molecular weight of 1450 g / ml. Aspect 52 52. The method of any one of aspects 25-51, wherein the composition is substantially free of one or more additional impurities. Aspect 53 53. The method of embodiment 52, wherein the one or more additional impurities are selected from the group consisting of RRT 0.32, RRT 0.43, RRT 0.82, RRT 0.86, and RRT 2.63. Aspect 54 54. The method of any one of aspects 25-53, wherein the composition comprises one or more antioxidants. Aspect 55 55. The method of embodiment 54, wherein the one or more antioxidants are present in an amount ranging from 0.01 to 5.0% w / w. Aspect 56 56. The method of claim 54 or 55, wherein the one or more antioxidants are selected from the group consisting of BHT and propyl gallate. Aspect 57 57. The method of any one of aspects 25-56, wherein the composition is formulated to deliver the naloxone free base locally. Aspect 58 58. The method of any one of aspects 25-57, wherein the composition is formulated to deliver the naloxone free base locally for 2 to 7 hours after application. Aspect 59 Aspect 59. The method of any one of aspects 25-58, wherein the composition is a cream, gel, lotion, or ointment. Aspect 60 60. The method of embodiment 59, wherein the composition is an ointment. Aspect 61 A kit comprising: a storage-stable non-aqueous topical composition according to any one of aspects 1 to 24; and Dispensing Devices and A kit comprising: Aspect 62 62. The kit of embodiment 61, wherein the dispensing device comprises a tube. Aspect 63 63. The kit of embodiment 62, wherein the tube comprises a squeezable tube.

[0007] Before the present invention is described in greater detail, it is to be understood that the invention is not limited to the specific embodiments described. It should be understood that these are not intended to be limiting and therefore may, of course, vary. As used herein, the scope of the present invention is limited only by the appended claims. It is also to be understood that the terminology used is for the purpose of describing particular embodiments only.

[0008] Where a range of values is provided, the upper and lower limits of that range are used unless the context clearly dictates otherwise. Each intermediate value between the lower limit and the lower limit, to one-tenth of the unit of the lower limit, and any value within this range It is understood that other stated or intermediate values are encompassed by the present invention. The upper and lower limits of smaller ranges may independently be included in the smaller ranges and are not necessarily included in the stated ranges. are also encompassed within the invention, subject to any specifically excluded limits within the ranges. Where the stated range includes one or both of the limits, any of those included limits shall Ranges excluding either or both are also included in the present invention.

[0009] Certain ranges are used herein with numerical values preceded by the term "about." The term "about" is used herein to refer to the exact number that it precedes, if any. and the literal meaning of the number whose term is near or approximate to the preceding number. Used to provide a reference to whether a number is close or approximate to a specifically enumerated number. When determining whether a near or approximate unenumerated number is to be used, the number must be It may be a number that, in the context of the number being recited, provides a substantial equivalent to the number specifically recited. do.

[0010] Unless otherwise defined, all technical and scientific terms used herein are defined by the The meanings described herein are the same as those commonly understood by those skilled in the art to which the invention pertains. Any methods and materials similar or equivalent to those can also be used in the practice or testing of the present invention. However, representative exemplary methods and materials are described below.

[0011] All publications and patents cited herein are to be interpreted as though each individual publication or patent were individually incorporated by reference. as if each such permission were specifically and individually indicated to be incorporated by reference. , which are incorporated herein by reference and disclose methods and / or materials. and those methods and / or materials which are incorporated herein by reference to describe them. The citation of any publication is for its disclosure prior to the filing date. and that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided are not intended to be an admission that The dates of publication may be different from the actual publication dates which may need to be confirmed by individual reviewers.

[0012] As used in this specification and the appended claims, the articles "a," "an," and " Please note that "the" and "the" include plural referents unless the context clearly dictates otherwise. The claims may be drafted to exclude any optional element. Please further note that this statement does not necessarily mean that the claim element is "exclusively" related to the enumeration of claim elements. for the use of exclusive terms such as "solely" and "only" or "negative" limitation.

[0013] As will be apparent to those skilled in the art upon reading this disclosure, the separate Each of the embodiments may be combined in various other embodiments without departing from the scope or spirit of the invention. A separate feature that can be easily separated from or combined with any of the features of the Any recited method may be implemented by the recited order of events or by the recited sequence of events. Any other order which is logically possible may be executed.

[0014] The apparatus and method are described with functional descriptions for grammatical fluidity, but are not intended to be limiting unless otherwise specified in U.S. Pat. Unless expressly recited under 35 U.S.C. 112, a claim does not necessarily have to be " should not be construed as limited by the interpretation of the "means" or "step" limitations, The full scope of the meaning and equivalents of the definitions provided by the claims under the doctrine of equivalents should be granted, and the claims are clearly written under 35 U.S.C. § 112. If the invention is invented, it should be given full legal equivalent under 35 U.S.C. 112. I want to make it clear that there is one thing.

[0015] In further describing various embodiments of the present invention, we first focus on the topical composition aspects. The methodology for delivering naloxone to a subject to treat a skin condition is reviewed in detail and then described. Embodiments using the compositions are described in detail, including the subject topical naloxone compositions. The kit is reviewed.

[0016] Topical Compositions As summarized above, aspects of the present invention involve the delivery of an amount of naloxone free base to a subject. The topical composition includes a topical composition for administering naloxone free base. Naloxone free base is described by the following formula:

[0017] [ka]

[0018] In embodiments, the subject naloxone compositions deliver naloxone free base locally to a subject. The term "topical" is used herein to refer to naloxone free salt. The group is delivered across the surface of the skin, e.g., subcutaneously, into the dermis, as well as into the stratum corneum, stratum germinativum, spinous layer, and The term "administration" has traditionally been used to refer to a route of administration that delivers the drug to one or more of the epidermis, including the stratum corneum, the basal layer, and the dermis. Thus, a topical composition having naloxone free base may be used, e.g. Apply to any convenient position such as arms, legs, buttocks, abdomen, back, neck, scrotum, face, behind ears, etc. In some embodiments, the skin is healthy, intact skin. In other embodiments, the skin comprises one or more layers (e.g., the stratum corneum, stratum germinativum, stratum spinosum, stratum basale, etc.). etc.) may be in a diseased state, an inflamed state, or a state that is not completely intact. The phrase "not completely intact" is used herein to refer to a portion of the skin that is not completely intact. that one or more layers contain at least one perforation due to disease, inflammation, or other condition It is used in its conventional sense to mean that skin that is not completely intact is, for example, Cumulatively, the amount of the naloxone composition applied to the surface area is 0.01% or more, e.g., topical naloxone. The Loxone composition is applied to 0.05% or more, for example 0.1% or more, for example 0. 0.5% or more, for example 1% or more, for example 2% or more, for example 3% or more, for example 5% or more, e.g. For example, 10% or more, for example, 25% or more, for example, 50% or more, for example, 75% or more, for example, 90% more than 95%, for example more than 97% (including more than 99%) of the skin The top layer may contain defective barrier properties (eg, perforations).

[0019] In certain embodiments, naloxone free base is delivered locally to the site of administration. The term "locally" is used herein to mean that naloxone is administered in the vicinity of the application site or at a site adjacent to the application site. It is used in its conventional sense to mean delivery into the proximal region of the body. In embodiments, naloxone free base is administered at a predetermined distance from the application site, for example, 30 minutes from the application site. Within cm, for example, within 25 cm, for example, within 20 cm, for example, within 15 cm, for example, within 10 Within cm, for example, within 5 cm, for example, within 4 cm, for example, within 3 cm, for example, within 2 cm , for example, within 1 cm, for example, within 0.5 cm (including within 0.1 cm) In other words, in these embodiments, the compositions of the present invention deliver naloxone to the administration site. It is administered locally with the intention of delivering it to a site at a distance from the site of application. The local penetration depth of the existing free base into the skin is also improved by the hydrophilic delivery vehicle (see below). ) can vary depending on the ingredients, from 0.01mm to 15mm, for example, from 0.05mm to 14. 5mm, for example 0.1mm~14mm, for example 0.5mm~13.5mm, for example 1mm ~13mm, for example 1.5mm~12.5mm, for example 2mm~12mm, for example 2.5 mm~11.5mm, for example 3mm~11mm, for example 3.5mm~10.5mm, for example 4mm to 10mm (including 5mm to 10mm penetration depth into the skin at the application site) In some cases, such administration may also be used to administer a low dose of naloxone. This may result in systemic administration of naloxone, such as intravenous administration.

[0020] In certain embodiments, featured topical compositions provide extended delivery of naloxone to a subject. The term "extended delivery" is used herein to refer to a drug that is administered over an extended period of time, e.g., For example, for several hours (including 1 hour or more), for example, 2 hours or more, for example, 3 hours or more, e.g. For example, for more than 4 hours, for example, for more than 5 hours, for example, for more than 6 hours, for example, for more than 7 hours The term "composition" is used to refer to a composition formulated to deliver a vasodilator. Therefore, the upper limit period may be, in some cases, 10 hours or less, e.g., 9 hours or less, e.g., 8 hours or less. In certain embodiments, the topical composition is, for example, naloxone for a period ranging from 1 to 10 hours, e.g., 2 to 9 hours, e.g., 2 to 7 hours The compound is formulated to deliver to a subject:

[0021] The application site and physiology of the subject, and the surface on the skin to which the subject naloxone compositions are applied. Depending on the area, the amount of naloxone free base in the topical composition of interest may vary. In some cases, the amount of naloxone ranges from 0.01 mg to 2000 mg, e.g., 0.02 mg. g to 1750 mg, e.g., 0.03 mg to 1500 mg, e.g., 0.04 mg to 1250 mg, for example 0.05 mg to 1000 mg, for example 0.06 mg to 750 mg, for example 0.07 mg to 500 mg, for example 0.08 mg to 250 mg, for example 0.09 mg to 1 In some embodiments, the range is from 0.01 mg to 50 mg. The amount of the free base is 1 mg to 200 mg, for example, 2.5 mg to 175 mg, for example, 5 mg to 1 50 mg, for example, in the range of 7.5 mg to 125 mg (including 10 mg to 100 mg) In some embodiments, the amount of naloxone free base is 0.0% by weight of the total topical composition. 1% w / w to 15% w / w, e.g., 0.05% w / w to 12.5% w / w, e.g., 0.0 5% w / w to 10% w / w (0.1% w / w to 10% w / w, e.g., 0.1% w / w to 5 % w / w (0.5% w / w to 5% w / w, e.g., 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.

[0022] In addition, the composition is substantially free of naloxone N-oxide. Cid has the following molecular formula: C 19 H 21 NO5 and is described by the following structural formula:

[0023] [ka]

[0024] The composition is substantially free of naloxone N-oxide, so that the naloxone N-oxide in the composition The amount of oxide, if present, is not more than 0.5 w / w, for example not more than 0.2 w / w (0.1 w / w In some examples, the composition comprises the process described in the experimental section below. A protocol was used to ensure that naloxone-N-oxide was not detectable in the formulation. does not contain detectable naloxone-N-oxide.

[0025] In some cases, the composition is shelf stable. Shelf Stability of Embodiments of the Invention The composition may be stored under storage conditions, for example, at room temperature under packaged sterile conditions, for a period of time, for example, 1 month. After storage for more than, e.g., 3 months or more (including more than, e.g., 6 months or more, e.g., 12 months or more), naloxone In some cases, the topical formulation is substantially free of the composition and and / or activator properties, e.g., color, viscosity, activator activity, etc., at room temperature and elevated temperatures, e.g. For example, temperatures above 40°C (including above 50°C) for a long period of time, for example, more than one week, more than two weeks, or Storage stable, remaining substantially unchanged for more than a month, more than six months, or more than a year .

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

[0027] In some cases, the non-aqueous vehicle includes a polyethylene glycol component. The term "polyethylene glycol" as used herein refers to linear polyethylene glycol, Branched polyethylene glycol, functionalized linear polyethylene glycol, or polyfunctionalized polyethylene glycol ethyleneoxy, branched polyethylene glycol, or any combination thereof It is used in the conventional sense to refer to a polymeric compound having a polymeric backbone structure.

[0028] Topical delivery vehicle compositions of interest include those having a concentration of 100 g / mol to 7500 g / mol, e.g. For example, 150g / mol to 5000g / mol, for example, 200g / mol to 2500g / mol l, for example, an average molecular weight of 300 g / mol to 1500 g / mol (e.g., the United States Pharmacopoeia The polyethylene glycol component has a polyethylene glycol having a molecular weight of 1.0. The term "average molecular weight" refers to the total weight of a polymer divided by the total number of molecules. is used in its conventional sense. In some embodiments, the polyethylene glycol moiety is 200g / mol to 2000g / mol, e.g., 300g / mol or 400g / mol Polyethylene glycols with an average molecular weight of 0.5 to 1500 g / mol are included. The average molecular weight of ethylene glycol can be determined by titration, size exclusion chromatography, high speed chromatography, among others. These include liquid chromatography, gel permeation chromatography, and mass spectrometry. It may be determined by any suitable molecular weight determination protocol, including but not limited to.

[0029] The polyethylene glycol component may be one or more different types of polyethylene glycol, e.g. For example, two or more different types of polyethylene glycol, for example, three or more different types of polyethylene glycol. polyethylene glycol, e.g., four or more different types of polyethylene glycol, e.g. 5 or more different types of polyethylene glycol (10 or more different types of polyethylene In certain embodiments, the subject naloxone compositions may include The polyethylene glycol component comprises a first polyethylene glycol and a second polyethylene glycol. In some such embodiments, the polyethylene glycol component The first polyethylene glycol (e.g., PEG 60) that is liquid below room temperature (RT) is added. 0 or less) and a second polyethylene glycol that is a waxy solid at or above RT (e.g., PEG 1000 or higher). In some embodiments, the first polyethylene The ethylene glycol component is a lower molecular weight copolymer having an average molecular weight of 1000 g / mol or less. of polyethylene glycol, and the second polyethylene glycol component is 1000g / Higher molecular weight polyethylene glycols have an average molecular weight of 100 mol or more. For example, the first polyethylene glycol component may have a molecular weight of 600 g / mol or less, e.g., 550 g / mol or less. ol or less, for example, 500 g / mol or less, for example, 450 g / mol or less, for example, 400 g / mol or less, for example 350 g / mol or less, for example 300 g / mol or less For example, the first polyethylene glycol may be The component is 200g / mol to 600g / mol, for example, 250g / mol to 500g / mol. mol, for example, a polyester having an average molecular weight in the range of 300 g / mol to 400 g / mol. In certain embodiments, the first polyethylene glycol component is polyethylene glycol. is a polyethylene glycol having an average molecular weight of 300 g / mol. In an embodiment, the first polyethylene glycol component has an average molecular weight of 400 g / mol. The second polyethylene glycol component is a polyethylene glycol having a molecular weight of 1000. g / mol or more, e.g., 1050 g / mol or more, e.g., 1100 g / mol or more, e.g., For example, 1150 g / mol or more, for example, 1200 g / mol or more, for example, 1250 g / mol or more, for example, 1300 g / mol or more, for example, 1350 g / mol or more, for example, 1400 Polyethylene glycol having an average molecular weight of 1450 g / mol or more, for example 1450 g / mol or more Coal (containing polyethylene glycol with an average molecular weight of 1500 g / mol or more) For example, the second polyethylene glycol component may be 1000 to 6000 g / mol, e.g., 1100g / mol to 4000g / mol, e.g., 1200g / mol ~3000g / mol, e.g., 1300g / mol~2000g / mol (1400g / Polyethylene glycol having an average molecular weight in the range of 1000 to 1500 g / mol (inclusive) In certain embodiments, the second polyethylene glycol moiety may be It is a polyethylene glycol with an average molecular weight of 450 g / mol. a first molecular weight, e.g., 300 or 500 g / mol, relative to the total amount of ethylene glycol; The percentage of polyethylene glycol is 20-90%, for example 30-70% (50-70%). The percentage of polyethylene glycol in the ol is, in some cases, 20-5 The first low molecular weight polyethylene glycol When the polyethylene glycol is combined with a second high molecular weight polyethylene glycol, the composition It may contain more of the first polyethylene glycol than the polyethylene glycol, e.g. For example, the amount of the first low molecular weight polyethylene glycol is less than the amount of the second high molecular weight polyethylene glycol. may exceed the amount of calls by, for example, 2% or more, for example, 5% or more (including 10% or more) .

[0030] In some cases, the storage-stable non-aqueous topical composition contains 0.1 to 1% by weight of nanoparticles. oxalic acid free base and 50-70% by weight of an average molecular weight of 300-400 g / mol First, polyethylene glycol and 30 to 45% by weight of an average molecular weight of 1450 g / ml and a second polyethylene glycol having the formula: 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% PEG14 50

[0031] In some embodiments, polyethylene glycol is compliant with regulatory agencies (e.g., the United States Pharmacopoeia Certified (i.e., Certificate of Analysis) by USP and National Formulary, European Pharmacopoeia, etc. It is a pharmaceutical grade polyethylene glycol with a molecular weight of 1.25g. In some cases, at least the first polyethylene glycol component is present when the composition is prepared. At this point, it contains little or no peroxide, e.g., 50 ppm Below, for example, 40 ppm or less (including 30 ppm or less, including 20 ppm or less, 10 ppm In an embodiment of the present invention, Commercially available polyethylene glycols that can be used in this process include Super Refined (TM) polyethylene glycol. Polyethylene glycol (Croda, East Yorkshire, England) nd), Emprove® Millipore polyethylene glycol (Me rck KGaA, Darmstadt, Germany), Pluriol (registered trademark) ) Polyethylene glycol (BASF), Japanese Pharmacopoeia Macrogol polyethylene glycol Includes Coal (NOF Corporation), etc.

[0032] Optionally, the non-aqueous delivery vehicle may include one or more antioxidants. If present, The amount of one or more antioxidants may in some cases be 0.01 to 5.0% w / w, e.g. The amount can vary from 0.02 to 2.0% w / w. Convenient antioxidants may be present, for example as described in the experimental section below. Examples of such antioxidants include butylated hydroxytoluene (BHT), propyl gallate, Examples include:

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

[0034] Topical naloxone compositions can be varied as desired. In some cases, The topical naloxone composition is an ointment. The term "ointment" refers to an application of naloxone to the skin or mucous membranes. It is used to refer to semi-solid preparations intended for topical application. In some cases, ointments exhibits a loss on drying of 25% or less, e.g., 20% or less. In some cases, the ointment , 300,000~2,000,000cp, e.g. 350,000~1,800,00 Viscosity ranges from 400,000 to 1,700,000 cp (including 400,000 to 1,700,000 cp). In some cases, the topical naloxone composition is a cream. The term refers to a semi-solid dosage form containing one or more active pharmaceutical ingredients dissolved or dispersed in a suitable base. In some cases, the cream contains 25,000 to 900,000 cp, for example, 30,000-800,000cp (50,000-700,000cp) In some cases, the topical naloxone composition exhibits a viscosity in the range of The term "lotion" refers to topical suspensions, solutions, and In some cases, lotions contain more than 40%, e.g., 50% In some cases, the lotion exhibits a loss on drying of 1,000 to 50,000% or more. 000cp, for example, 2,000-40,000cp (including 5,000-30,000cp) In some cases, the topical naloxone composition may be a gel. The term "gel" refers to large particles interpenetrated by small inorganic particles or liquids. A gel is a semi-solid system consisting of a suspension of organic molecules. , exhibiting a loss on drying of 60% or more, for example 70% or more. Viscosity in the range of 5,000 to 100,000 cp, e.g., 5,000 to 70,000 cp In certain cases, the topical naloxone composition is formulated as a liquid and It may be dispensed as a spray, aerosol, or foam.

[0035] Topical naloxone compositions according to embodiments of the present invention are applied to the skin of a subject at the application site. Skin irritation is defined herein as, for example, redness (erythema), pain, swelling, Generally refers to adverse reactions to the skin such as swelling (edema), dryness, discoloration, or damage. Thus, the subject topical compositions are intended to be used in a variety of ways when applied to the skin of a subject. In this case, skin quality remains normal and topical delivery of naloxone is consistent throughout the dosing interval. It is formulated to maintain

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

[0037] In certain embodiments, the subject topical naloxone compositions are first applied to a patch. , can be applied to the skin site of a subject, or to the skin to which the topical naloxone composition has been applied. A patch may be placed over the site. The patch may be made from a material that does not absorb naloxone. Patches of interest include, but are not limited to, nonwoven fabrics, woven fabrics, films (including sheets), ), obtained by laminating a film onto a porous body, foam, paper, nonwoven fabric or woven fabric. Nonwovens include polyethylene and polypropylene composites, and combinations thereof. Polyolefin resins such as propylene; polyethylene terephthalate, polybutylene terephthalate Polyester resins such as polyethylene terephthalate and polyethylene naphthalate; rayon, polyamide Poly(ester ether), polyurethane, polyacrylic resin, polyvinyl alcohol Styrene-isoprene-styrene copolymer, and styrene-ethylene-propylene copolymer The fabric may comprise a polyester-styrene copolymer, a polyester-styrene copolymer, and combinations thereof. Polyvinyl alcohol, polyacrylic resin, polyester resin, and combinations thereof The film may comprise a laminate of polyolefins such as polyethylene and polypropylene. Polyacrylate resins such as polymethyl methacrylate and polyethyl methacrylate Resins: polyethylene terephthalate, polybutylene terephthalate and polyethylene naphtha Polyester resins such as phthalate; as well as cellophane, polyvinyl alcohol, ethylene ethylene-vinyl alcohol copolymer, polyvinyl chloride, polystyrene, polyurethane, Acrylonitrile, fluororesin, styrene-isoprene-styrene copolymer, styrene ethylene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymer, polyamide, and polysulfone, as well as combinations thereof. This includes wood-free paper, kraft paper, Japanese paper, glassine paper, synthetic paper, and combinations of these. In some embodiments, the patch is an occlusive material.

[0038] The size of the patch varies depending on the area on the skin to which the topical naloxone composition is applied. In some cases, the patch may be sized to cover the entire application site on the subject. Therefore, the patch may have a length ranging from 2 to 100 cm, for example from 4 to 60 cm, and and width in the range of 2 to 100 cm, for example 4 to 60 cm. The area is 4cm 2 ~1000cm 2 , for example 5cm 2 ~500cm 2 , for example 10cm 2 ~ 250cm 2 , for example 15cm 2 ~100cm 2 (20cm 2 ~50cm 2 (including It may be a box.

[0039] Methods for applying topical naloxone compositions Aspects of the present invention also include methods for applying the topical naloxone compositions of the present invention to a subject. As mentioned above, topical refers to the route of administration where naloxone is delivered across the skin, e.g. For example, one of the subcutaneous tissue, the dermis, and the epidermis, including the stratum corneum, stratum germinativum, stratum spinosum, and stratum basale. Thus, the method includes administering the subject naloxone compositions to the arms, legs, buttocks, shoulders, or other areas of the body. Apply to skin areas such as the waist, thighs, abdomen, back, neck, scrotum, face, and behind the ears. In some embodiments, the method comprises applying a composition of the present invention to healthy, intact skin. In other embodiments, the method includes removing one or more layers (e.g., stratum corneum, stratum germinativum, stratum spinosum, stratum corne ... layer, basal layer, etc.) may be in a diseased, inflamed, or not fully intact state. Skin, e.g., where one or more layers, such as the stratum corneum, are defective due to disease, inflammation, or other conditions The method includes applying the subject compositions to skin that contains barrier properties (e.g., perforations) that provide a barrier to the skin. The method comprises: applying a topical naloxone composition to the skin in one or more layers; 0.01% or more, e.g., 0.05% of the surface area to which the topical naloxone composition is applied or more, e.g., 0.1% or more, e.g., 0.5% or more, e.g., 1% or more, e.g., 2% or more, e.g. For example, 3% or more, for example, 5% or more, for example, 10% or more, for example, 25% or more, for example, 50% or more Above, for example, 75% or more, for example, 90% or more, for example, 95% or more, for example, 97% or more (99 % or more) to a subject's skin surface that contains defective barrier properties (e.g., perforations) This may include:

[0040] When describing the methods of the present invention, the term "subject" refers to a subject to which a topical composition is applied and to which the subject comes into contact. Therefore, the subject matter of the present invention is not limited to these. mammals, e.g., humans and other primates, e.g., chimpanzees and other apes, but not may include monkeys and ape species, dogs, rabbits, cats and other domesticated pets, etc. In certain embodiments, the subject is a human. The term subject also refers to a subject of any age, body type, The term "subject" refers to any person or organism with a specific weight or other physical characteristics, and includes adults, children, or both. The subject may be a child, infant, or newborn.

[0041] As described above, the methods of the present invention involve applying a topical naloxone composition to the skin surface of a subject. and administering the topical composition to the subject for a period of time sufficient to deliver naloxone to the subject. In some embodiments, the method comprises maintaining the subject in contact with a skin site. "Extended transdermal delivery" refers to the extended delivery of naloxone to the skin over an extended period of time. For example, more than 1 hour, for example, more than 2 hours, for example, more than 3 hours, for example, more than 4 hours for several hours, including, for example, 5 hours or more (including 6 hours or more, e.g., 7 hours or more). For example, a topical composition may be formulated to provide delivery of loxone. , 0.1 hours to 20 hours, for example, 0.5 hours to 15 hours, for example, 1 hour to 10 hours, for example It is formulated to deliver naloxone to a subject's skin site for a duration of, for example, 2 to 7 hours. obtain.

[0042] In certain embodiments, a protocol may include multiple dosing intervals. "Separate" refers to a method in which two or more doses of a topical composition are applied to a subject sequentially and maintained in contact with the subject. Therefore, the first application of the topical composition is in contact with the subject. It is removed from the skin (e.g., rinsed with water or wiped with a damp cloth) and used as a topical A second dose of the composition is applied to the skin surface of the subject. The regimen may consist of two or more dosing intervals, e.g., three or more dosing intervals, e.g., four or more dosing intervals. , for example, 5 or more dosing intervals (including 10 or more dosing intervals).

[0043] The duration between dose intervals in a multiple dose interval treatment protocol may vary depending on the subject's physiology. The duration of treatment may vary depending on the individual or treatment protocol as determined by the healthcare professional. For example, the duration between dose intervals in a multiple dose treatment protocol may be predetermined. The time between doses may vary, or may follow regular intervals. It can be 1 hour or more, for example 2 hours or more, for example 4 hours or more, for example 6 hours or more, for example 8 hours or more, for example 12 hours or more, for example 16 hours or more (including 24 hours or more) In certain embodiments, the multiple dosing interval protocol may include one or more dosing intervals, e.g., For example, more than 2 days, for example, more than 3 days, for example, more than 4 days, for example, more than 5 days, for example, more than 6 days, for example, For example, the time between doses may be 7 days or more, such as 10 days or more (including 30 days or more). The upper limit of the time between dose intervals may in some cases be 30 days or less, e.g., 28 days or less, For example, within 21 days, for example, within 14 days, for example, within 7 days (including within 3 days). In certain embodiments, the time between dosing intervals is, for example, 2 to 30 days, e.g., 3 to 28 days. For example, it is in the range of 4 to 21 days, for example, 5 to 14 days (including 6 to 10 days). In certain cases, the duration between dosing intervals may vary depending on the specific condition (described in more detail below). If the progression of treatment (as indicated), skin sensitivity, dry skin, or symptoms of the treated condition persist It may depend on the degree of relief (e.g., reduction in itching).

[0044] Applying and maintaining a topical naloxone composition in contact with a subject, according to certain embodiments The method for treating inflammatory skin diseases, non-inflammatory skin diseases, pruritus, or inflammatory skin diseases Treatment of skin conditions such as pruritus, non-inflammatory skin diseases, or one or more symptoms associated with pruritus For example, in some cases the method is used in the treatment or prevention of inflammatory skin diseases, For example, to treat or prevent atopic dermatitis, eczema, psoriasis, or a combination thereof. In other cases, the method includes applying a topical composition to the skin surface of a subject to treat the condition. The method comprises administering a topical composition to a subject to treat or prevent a non-inflammatory skin condition, such as chronic prurigo. In still other cases, the method comprises applying the topical nanoparticles described above to the surface of the skin of the elephant. topical treatment of pruritus by applying one or more of the loxone compositions to the skin of a subject; In certain cases, the pruritus is caused by primary biliary tract infections. liver cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, Pruritus associated with one or more of the following: parasites, neurological conditions, or pregnancy. In embodiments, the pruritus is drug-induced pruritus or pruritogen-induced pruritus. In certain embodiments, the pruritus is caused by shingles, psoriasis, hives, dysesthesias, glaucoma, psoriasis, hives, psoriasis, rash ... Associated with conditions selected from Lova's disease, chronic kidney disease, and Hailey-Hailey disease. Pruritus can be characterized by redness of the skin, raised skin, patches or blisters, dry or cracked skin, leathery or The method may involve redness of the skin accompanied by pruritus, scaly or flaky skin. Bumps, spots or blisters, dry or cracked skin, leathery or scaly skin and administering a sufficient amount of the subject naloxone composition to treat one or more of the following: It can be seen.

[0045] In a method of treating a skin condition according to certain embodiments, a topical naloxone composition The substance may be applied to an affected area of skin (e.g., an inflammatory skin condition, a non-inflammatory skin condition, or a pruritic condition). The topical composition may be applied directly to all or part of the affected area of the skin, e.g. For example, more than 5% of the affected area of the skin, for example more than 10%, for example more than 25%, for example more than 50%, For example, it applies to 75% or more, 90% or more, 95% or more (including 99% or more). In some cases, the topical composition is applied to the entire affected area of skin. In certain cases, the treatment may be applied to an area of the skin that is larger than the affected area, e.g., directly onto the affected skin area. The amount of adjacent skin surface, e.g., an additional 5% or more of the surrounding area on the skin (depending on the size of the affected skin) additional 10% or more, for example additional 15% or more (based on the additional perimeter area on the skin) The topical composition is applied to the skin (including at least 25% of the skin).

[0046] The term "treatment" as used herein refers to the treatment of a condition in which a subject is suffering from a condition, including at least one of the following: is used in its conventional sense to mean that at least some improvement is achieved, where improvement is Refers to at least a reduction in a parameter related to the condition being treated, e.g., the magnitude of a symptom Therefore, treatment also refers to the treatment of a condition in which the subject is no longer in a good condition, or at least The pathological condition, or at least the symptoms that characterize it, must be eliminated. The term "manage" as used herein includes situations in which symptoms associated with is when the symptoms associated with the condition from which the subject suffers are at least controlled (i.e. used in its traditional sense to mean that the severity of symptoms remains within a predetermined level In some cases, symptoms are improved without eliminating the underlying condition.

[0047] The term "prevention" is used herein to mean that the subject topical compositions provide a preventative effect on the skin surface of a subject. It is applied effectively and completely prevents the indicated skin condition from occurring or is associated with the condition. A reduction in the severity of a particular condition or symptom is experienced by the subject. It is used in its traditional sense to mean the reduction or complete elimination of occurrence. In certain embodiments, the method further comprises assessing the severity of the condition or symptoms associated with the condition by administering the 5% or more as determined by a healthcare professional (e.g., size of affected skin, amount of inflammation, etc.) based on), e.g. 10% or more, e.g. 15% or more, e.g. 25% or more, e.g. 50% or more For example, 75% or more, 90% or more, 95% or more (including 99% or more) and prophylactically applying a subject topical naloxone composition sufficient to In some embodiments, applying a topical naloxone composition in accordance with the subject method improves the condition or It is sufficient to completely eliminate the occurrence of any symptoms related to the skin disease. In embodiments of the present invention, prophylactically applying a topical naloxone composition to a skin surface of a subject comprises: For example, 0.1 days or more, for example, 0.5 days or more, for example, 1 day or more, for example, 2 days or more, for example, 3 days days or more, for example, 4 days or more, for example, 5 days or more, for example, 6 days or more, for example, 7 days or more (14 days or more) In other embodiments, the subject Prophylactic application of a topical naloxone composition to the skin surface of a subject is effective in treating skin conditions such as itching. For example, topical application to the skin surface of a subject is sufficient to reduce the severity of symptoms associated with The prophylactic application of the naloxone composition may be more than once per hour, e.g., more than once per hour. more than twice per hour, for example more than three times per hour, for example more than five times per hour, for example more than one time per hour 10 times or more per hour, e.g. 15 times or more per hour, e.g. 25 times or more per hour, e.g. For example, 50 times or more per hour (including 100 times or more per hour), depending on the skin condition It may be sufficient to reduce the number of times the skin surface is scratched. When used in conjunction with topical naloxone compositions, the topical naloxone compositions may be used to treat symptoms associated with pruritus, such as rash, redness, scaly skin, blisters or bumps) for more than one hour before the onset of symptoms, including For example, more than 3 hours ago, for example, more than 6 hours ago, for example, more than 12 hours ago (including more than 24 hours ago) The composition may then be applied to the skin surface of a subject for symptomatic treatment.

[0048] In embodiments, the topical composition is used to treat a skin condition or its associated symptoms (e.g., a drug or At least one hour, for example, two hours, before the onset of pruritus (itching induced by a pruritic substance) is expected. , for example, more than 4 hours ago, for example, more than 6 hours ago, for example, more than 8 hours ago, for example, more than 12 hours ago For example, more than 16 hours ago, for example, more than 20 hours ago, for example, more than 24 hours ago (more than 48 hours ago) It may be applied prophylactically to the skin surface of a subject, including before or after use.

[0049] In some embodiments, the method comprises administering topical naloxone in the treatment or prevention of pruritus. The method includes applying a composition to the skin surface of a subject. The pruritus is caused by primary biliary cirrhosis, chronic liver disease, or other conditions. Renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, neurology It may be associated with one or more of the following conditions: In certain embodiments, the naloxone composition may be a substance-induced pruritus. Skin redness, bumps, spots or blisters, dry or cracked skin, leathery or Formulated to treat or prevent one or more of the following: scaly or scaly textured skin In these embodiments, applying the topical naloxone composition is effective in treating pruritus. Severity is measured by, for example, 5% or more (e.g., patient response survey, scratching of the skin surface during a given period). depending on the number of times), e.g., 10% or more, e.g., 15% or more, e.g., 25% or more, e.g., 50 % or more, for example, 75% or more, for example, 90% or more, for example, 95% or more (including 99% or more) In certain cases, topical naloxone compositions may be applied to the skin surface. Applying and maintaining contact with the surface is sufficient to relieve the pruritus. Applying the subject topical naloxone compositions may be done one or more times per hour, e.g., one or more times per hour. more than twice per hour, for example more than three times per hour, for example more than five times per hour, for example More than 10 times per hour, e.g., more than 15 times per hour, e.g., more than 25 times per hour , e.g., 50 or more times per hour (including 100 or more times per hour), depending on pruritus The method is sufficient to prevent pruritus by reducing the number of times the skin surface is scratched. When used in conjunction with topical naloxone compositions, the topical naloxone compositions may be used to treat symptoms associated with pruritus, such as At least 1 hour before the onset of itching, for example, at least 3 hours before, for example, at least 6 hours before, for example, 12 applied to the subject's skin surface at least 24 hours before the onset of symptoms obtain.

[0050] In other embodiments, the method is for treating inflammatory skin conditions such as atopic dermatitis, eczema, or psoriasis. applying a topical naloxone composition to the skin surface of a subject in the treatment or prevention of a condition. In certain embodiments, the skin condition is atopic dermatitis associated with pruritus. In some cases, the naloxone composition may be used to treat atopic dermatitis, eczema, or dry skin. Treat or prevent symptoms associated with inflammatory skin conditions, such as itching caused by scabies In these embodiments, the topical naloxone composition is formulated to This refers to the severity of symptoms (e.g., itch) associated with an inflammatory skin condition, measured by a reduction of, for example, 5% or more (e.g., For example, patient response surveys, the number of times the skin surface is scratched during a given period), e.g., 10% or more, e.g., 15% or more, e.g., 25% or more, e.g., 50% or more, e.g., 75% or more, e.g. For example, a reduction of 90% or more, such as 95% or more (including 99% or more), is sufficient. In certain cases, topical naloxone compositions are applied to and maintained in contact with the skin surface. This is sufficient to relieve symptoms (e.g., itching) associated with the inflammatory skin condition. For example, applying a subject topical naloxone composition may be performed one or more times per hour, e.g., one or more times per hour. For example, more than twice per hour, for example, more than three times per hour, for example, more than five times per hour, For example, more than 10 times per hour, for example, more than 15 times per hour, for example, more than 2 times per hour 5 or more times, e.g., 50 or more times per hour (including 100 or more times per hour), inflammatory To reduce the number of times the skin surface is scratched in response to itching caused by a skin condition is sufficient.

[0051] In yet other embodiments, the method further comprises administering to a subject a therapeutically effective amount of ... Inflammatory skin conditions that are found to be partially or completely resistant to treatment with other active agents applying a topical naloxone composition to the skin surface of a subject in the treatment or prevention of In these embodiments, applying a topical naloxone composition described herein is a steroid, anti-inflammatory or immunosuppressant administered to a subject to treat a skin condition For example, the amount of 5% by weight or more, for example, 10% by weight or more, for example, 25% by weight or more, for example, 5 0% by weight or more, for example 75% by weight or more, for example 90% by weight or more (including 95% by weight or more) In certain embodiments, the subject topical naloxone compositions are Applying and maintaining on the skin surface is effective against inflammation caused by steroids, anti-inflammatory or immunosuppressive agents. It is sufficient to completely replace the treatment of infectious skin conditions.

[0052] In certain instances, the method comprises applying a topical naloxone composition described herein. in the treatment of inflammatory skin conditions (e.g., atopic dermatitis, eczema, psoriasis) by One or more doses of steroid therapy, anti-inflammatory or immunosuppressant drugs administered by, for example, 2 or more times, e.g., 3 or more times, e.g., 4 or more times, e.g., 5 or more times, e.g., 6 or more times, e.g. 7 or more times, e.g., 8 or more times, e.g., 9 or more times, e.g., 10 or more times, e.g., 15 or more times, e.g. For example, 25 or more times, for example, 50 or more times, for example, 75 or more times (including 100 or more times), inflammation steroid therapy, anti-inflammatory or immunosuppressant drug schedules for treating chronic skin conditions Thus, the topical naloxone described herein includes replacing previously administered doses. Applying and maintaining the composition provides a steroid therapeutic agent in the treatment of inflammatory skin conditions, Reduce the number of scheduled doses of anti-inflammatory or immunosuppressive drugs by more than 5%, e.g., 10%. Above, for example, 15% or more, for example, 20% or more, for example, 25% or more, for example, 50% or more, for example for example by more than 75%, such as by more than 90%, such as by more than 95% (for treating inflammatory skin conditions) The number of scheduled doses of steroid therapy, anti-inflammatory drugs, or immunosuppressants in This may be sufficient to reduce the

[0053] In certain embodiments, the subject methods involve the topical naloxone compositions described herein. In the treatment of inflammatory skin conditions caused by It is suitable for completely replacing the

[0054] In certain embodiments, the method includes administering to a subject a steroid treatment in the treatment of an inflammatory skin condition, an anti-inflammatory drug, or a combination thereof. In conjunction with the administration of an inflammatory or immunosuppressant agent, one or more of the subject topical naloxone compositions In some cases, the topical naloxone composition comprises applying and maintaining the a reduced dose of a steroid in the treatment of an inflammatory skin condition when contacted with a subject; An anti-inflammatory or immunosuppressant may be administered to the subject, for example, a steroid, anti-inflammatory or immunosuppressant. The dose of each scheduled administration of immunosuppressant may be 5% or more, for example 10% or more, for example 15% or more. % or more, for example, 20% or more, for example, 25% or more, for example, 50% or more (including 75% or more) In some cases, the administration of steroids, anti-inflammatory drugs or immunosuppressants One or more of the scheduled medications, e.g., for each scheduled medication , every 2 scheduled doses, every 3 scheduled doses, every 4 scheduled doses The doses are excluded (i.e., skipped) after each dose taken or at some other interval. In certain cases, one or more of the subject topical naloxone compositions may be applied. Use of steroids, anti-inflammatory drugs, or immunosuppressants is not recommended as a continuous scheduled Two or more consecutive schedules of medication, such as steroids, anti-inflammatory drugs, or immunosuppressants scheduled doses, e.g., three or more consecutive scheduled doses (four or more consecutive scheduled doses) It is sufficient to eliminate the risk of steroid use (including scheduled medication).

[0055] In certain embodiments, the compositions of the invention are used to treat the same or unrelated conditions. It may be administered before, simultaneously with, or after the other therapeutic agent. When used in combination, the subject topical naloxone compositions may be administered in the same or different compositions. Therefore, naloxone compositions and other therapeutic agents of interest may be addressed through combination therapy. "Combination therapy" refers to the treatment of a combination of substances in a subject receiving therapy. It is intended that the drug be administered to a subject in a manner that will produce a beneficial effect. For example, combination therapy may involve the administration of a particular drug regimen. In accordance with the present invention, the naloxone compositions of the present invention may be combined to form a therapeutically effective dosage. at least one other drug, such as an anti-inflammatory drug, an immunosuppressant, among other types of therapeutic agents; Administration with a pharmaceutical composition containing a steroid, an analgesic, an anesthetic, an antihypertensive, or a chemotherapeutic agent The therapeutic effect of the combination of these substances on the subject undergoing therapy can be achieved by The administration of the separate pharmaceutical compositions may occur at the same time or at different times (i.e. The tests can be performed sequentially, on the same day or on different days, in any order.

[0056] When the naloxone composition is administered simultaneously with a second therapeutic agent to treat the same condition , the weight ratio of naloxone to the second therapeutic agent is 1:2 to 1:2.5, 1:2.5 to 1:3, 1 :3~1:3.5, 1:3.5~1:4, 1:4~1:4.5, 1:4.5~1:5, 1 :5 to 1:10, and 1:10 to 1:25, or ranges thereof. For example, the weight ratio of naloxone to the second therapeutic agent may be 1:1 to 1:5, 1:5 to 1:10, or 1:1 The ratio may range from 0 to 1:15, or from 1:15 to 1:25. Alternatively, the second treatment The weight ratio of drug to naloxone is 2:1 to 2.5:1, 2.5:1 to 3:1, or 3:1 to 3.5. :1, 3.5:1~4:1, 4:1~4.5:1, 4.5:1~5:1, 5:1~10: 1, and 10:1 to 25:1, or ranges thereof. For example, The weight ratio of Loxone is 1:1 to 5:1, 5:1 to 10:1, 10:1 to 15:1, or It can range from 15:1 to 25:1.

[0057] As discussed above, aspects of the present invention provide a method for delivering naloxone to a subject over a period of time sufficient to achieve the desired effect. In some embodiments, the method comprises administering a topical naloxone composition to a subject. The method delivers a targeted dosage of naloxone to the topical skin surface of a subject, e.g., a total topical drug To deliver a target dose determined by exposure or by average daily local drug exposure The method includes maintaining the topical composition in contact with the subject in a manner sufficient to

[0058] In some embodiments, the topical naloxone composition is administered to a subject when applied to the skin surface. In this case, the composition is a naloxone composition containing a hydrophobic delivery vehicle such as petrolatum. For example, the formulation may be formulated to exhibit less transepidermal water loss than those shown herein. The topical naloxone compositions described herein are intended to provide a therapeutically effective amount of naloxone that, when applied to the skin surface of a subject, provides a 0.5 g / m 2 / hour or more, e.g., 1g / m 2 / hour or more, e.g. 1.5g / m 2 / hours or more, For example, 2 g / m 2 / hour or more, e.g. 3g / m 2 / hour or more, e.g. 5g / m 2 / hours or more Above, for example, 10 g / m 2 / hour or more (25g / m 2 / hour or more), hydrophobic delivery vehicle exhibits less transepidermal water loss than that exhibited by naloxone compositions containing naloxone In some embodiments, the topical formulation is formulated to be effective when applied to the skin surface of a subject. The naloxone composition for use is 25 g / m 2 / hour or less, e.g. 20g / m 2 / hour or less, e.g. 15g / m 2 / hour or less, e.g. 10g / m 2 / hour or less (5g / m 2 / hours or less This indicates transepidermal water loss (including

[0059] In some embodiments, the method comprises administering a topical naloxone composition to a subject in a predetermined amount of naloxone. The protocol may include maintaining the compound in contact with the subject in a manner sufficient to deliver the compound. When the method involves delivering a predetermined amount of naloxone to a subject, the local delivery amount of naloxone is , 0.001mg to 2mg, for example 0.005 to 1.9mg, for example 0.01mg to 1. 8mg, for example 0.05-1.7mg, for example 0.1mg-1.6mg, for example 0.5mg The amount may be in the range of 0.5 mg to 1 mg (including 0.5 mg to 1 mg).

[0060] In certain embodiments, the amount of naloxone delivered to the subject is It can be a percentage of the total amount of naloxone present. For example, The amount of naloxone to be administered is not less than 1% of the total amount of naloxone present in the topical composition, e.g. For example, 2% or more, such as 5% or more, such as 1% or more, of the total amount of naloxone present in the topical composition. 0% or more, for example 25% or more (including 50% or more). , delivering 5% or more of the naloxone in the topical composition locally to the target over a single dosing interval. and maintaining the naloxone composition in contact with the subject in a manner sufficient to For example, if the topical composition contains 1 mg of naloxone, the method may include administering 1 mg of naloxone over the dosing interval. Thus, 0.05 mg or more of naloxone in the topical composition, e.g., 0.1 mg or more, e.g., 0.25 mg or more, for example, 0.4 mg or more, for example, 0.45 mg or more (0.5 mg or more and administering the topical composition to a subject in a manner sufficient to locally deliver naloxone (including This may include maintaining contact with the elephant.

[0061] In certain embodiments, each of the above-described subject methods further comprises administering a topical composition at the end of a dosing interval. The topical composition may further include removing the article from contact with the subject. , 0.1 hours or more, for example 0.5 hours or more, for example 1 hour or more, for example 2 hours or more, for example For example, more than 4 hours, for example, more than 6 hours, for example, more than 8 hours, for example, more than 12 hours, for example, more than 16 hours The topical composition is in contact with the subject for a period of time or more, such as 20 hours or more (including 24 hours or more). The contact may be maintained and then removed.

[0062] As noted above, the dosing interval is a single dose in which the topical composition is applied and maintained in contact with the subject. This involves applying a topical composition to the skin of a subject, When removed from contact with the subject, or when all of the naloxone in the composition is released locally to the subject, In certain embodiments, the protocol ends when the dose is delivered. In practicing the methods of the present invention, a treatment regimen may include two or more dosing intervals, e.g. For example, three or more dosing intervals, for example, four or more dosing intervals, for example, five or more dosing intervals (10 and / or a dosing interval of at least 10 minutes.

[0063] In certain cases, subsequent dosing intervals in a treatment regimen may be longer than the previous dosing interval. For example, the concentration of naloxone may be: In subsequent dosing intervals, the decrease is 10% or more, for example 20% or more, for example 50% or more, for example 7 It may be increased by 5% or more, for example by 90% or more (including 100% or more). The upper limit of the increase in naloxone concentration in some cases is less than 10-fold, e.g. For example, 5 times or less, for example, 2 times or less, for example, 1 time or less, for example, 0.5 times or less (0.25 times or less) (including

[0064] Meanwhile, the concentration of naloxone may increase by, for example, 10% or more, for example, 20%, in subsequent dosing intervals. % or more, for example, 50% or more, for example, 75% or more, for example, 90% or more (including 100% or more) The upper limit of the decrease in naloxone concentration in subsequent dosing intervals is In some cases, 10 times or less, for example 5 times or less, for example 2 times or less, for example 1 time or less, e.g. For example, 0.5 times or less (including 0.25 times or less).

[0065] In other cases, subsequent dosing intervals may be performed with different dosages of polyethylene glycol, as described above. The type of naloxone free base, amount of polyethylene glycol, and other information about the dosage interval may be different from the previous one. The formulation may include:

[0066] In some embodiments, the skin is any area of the skin to which the topical naloxone composition is applied. To assess changes, for example, skin texture or color at the application site and topical nanoparticles may be administered. Any injury, pain, swelling or dryness is alleviated by maintaining the oxalic composition in contact with the subject. In certain embodiments, the skin is evaluated to determine whether dryness is alleviated. It is evaluated to assess transepidermal water loss due to

[0067] The application site may be evaluated at any time during the subject method. The skin should be treated periodically, e.g., every 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours. every 12 hours, every 24 hours (including every 72 hours), or some other interval The topical composition is evaluated while in contact with the subject by observation or palpation. For example, applying a topical composition to a subject while maintaining the topical composition in contact with the subject. 15 minutes after applying the topical composition, 30 minutes after applying the topical composition, 1 hour after application of the topical composition, 2 hours after application of the topical composition, and 4 hours after application of the topical composition after application of the topical composition, 8 hours after application of the topical composition, 12 hours after application of the topical composition (topical The application site may be evaluated up to (including 24 hours after application of the desired composition).

[0068] In other embodiments, the site of topical application may be maintained at a constant temperature for 20 minutes after the topical composition is removed from contact with the subject. For example, the application site is evaluated 30 minutes after removing the topical composition, e.g., 1 hour after removing the topical composition, e.g., 2 hours after removing the topical composition, e.g., 4 hours after removing the topical composition, e.g., 8 hours after removing the topical composition, e.g., For example, 12 hours after removing the topical composition (24 hours after removing the topical composition) may be evaluated as follows:

[0069] In some embodiments, the site to which the topical composition is applied is The topical composition is evaluated before application to the subject to record skin color and texture. For example, the application site may be 5 minutes before applying the topical composition, e.g., 10 minutes ago, for example, 30 minutes ago, for example, 60 minutes ago, for example, 120 minutes ago, for example, 240 minutes ago (4 The method may include multiple dosing intervals where the dose is applied sequentially. In this case, the application site should be monitored after each removal of the topical composition from the skin and after each subsequent application of the topical composition. The drug may be evaluated before it is applied. For example, when the first topical composition is removed, The application site should be 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, etc. after removal. The subsequent topical compositions may be evaluated before applying the second topical composition. The test may be applied to the previous application site immediately after assessing the skin, or after a predetermined time period after assessing the skin. For example, after evaluating the skin, It may be applied after 12 hours, 18 hours, or 24 hours.

[0070] In some cases, the method includes determining the severity of the condition being treated after administration of the topical composition. assessing the condition, for example, to determine that the composition is effective in treating the condition in a subject. Thus, the method includes administering the topical composition to a patient suffering from an inflammatory skin condition, a non-inflammatory skin condition, or itching. or one or more conditions associated with inflammatory skin disease, non-inflammatory skin disease or pruritus The assessment may include assessing the severity of a subject's skin condition, such as rash. In some cases, the method is directed to treating atopic dermatitis, eczema, psoriasis, or a combination thereof. In other cases, the method includes assessing the severity of an inflammatory skin disease, such as chronic prurigo. In still other cases, the method includes assessing the severity of any non-inflammatory skin condition. In certain cases, the pruritus is caused by a primary Primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, poverty It is pruritus associated with one or more of the following conditions: blood, parasites, neurological conditions, or pregnancy. In certain embodiments, the pruritus is drug-induced pruritus or pruritogen-induced pruritus. In certain embodiments, the pruritus is caused by shingles, psoriasis, hives, or back pain. associated with conditions selected from: schizophrenia, Grover's disease, chronic kidney disease, and Hailey-Hailey disease Pruritus may include redness of the skin, raised skin, patches or blisters, dry or cracked skin, or a rash. The method may involve the development of a flaky or scaly textured skin, and the skin rash associated with pruritus. Redness, bumps, spots or blisters, dry or cracked skin, leathery or scaly texture and applying a subject naloxone composition in an amount sufficient to treat one or more of the affected areas of the skin. It may also include.

[0071] kit Kits for use in the practice of certain methods described herein are also provided. In certain embodiments, the kit includes one or more topical naloxones, e.g., as described above. In certain embodiments, the kit includes a dropper or metered dispenser. In some cases, the topical naloxone composition is administered by a squeeze device. of a squeezable tube, e.g., a squeezable tube configured to hold an ointment The kit also includes a sponge, brush, doctor blade, spreading device, flat The present invention may include an applicator such as a lubricating device, a greaser, or a combination thereof. In embodiments, the kit includes a waterproof adhesive sheet that can be used to cover the application site of the topical composition. This also includes overlays such as overlays.

[0072] In a given kit containing two or more of the subject topical compositions, the compositions are individually packaged. In certain embodiments, the kit may comprise a main Providing instructions for practicing the subject method or the means to obtain them (e.g., instructions) These instructions also include the website URL that directs users to the web page. It may be printed on a substrate, the substrate being one of a package insert, a package, a reagent container, etc. In the subject kits, one or more components may be present in any convenient or desirable form. The components may be present in the same or different containers, as appropriate.

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

[0074] experiment A. Detection of Decomposition Products First, all components except PEG1450 (e.g., low MW PEG, NLX, and Add other additives (e.g., antioxidants, glycerol, citric acid, etc.) at room temperature and stir. The formulations described in further detail below were prepared by adding PEG 1450 to the The mixture was heated to approximately 50°C until all the PEG1450 was dissolved. Once formed, it was passed through a tube (from Albea) with a 0.305 inch orifice. The mixture was filled into a 1-inch laminate tube and sealed with foil. The inner layer of the laminate was a linear The filled tube was cooled to room temperature and then An opaque ointment formed within the tube.

[0075] Stability studies of PEG-based naloxone ointment formulations were performed at 25°C, 40°C, and 60°C. The formation of one particular decomposition product (also called a "related substance") occurs under these temperature conditions. This related substance was typically observed within 1 week of formulation preparation. Using primarily HPLC, we have shown that increases in temperature and humidity affect the activity of naloxone and It was found that the amount of degradation products was further increased compared to the control. formed at low levels and consistently across a range of excipients and storage conditions. Over time, a small percentage of naloxone is chemically decomposed by an oxidation process. It is thought that the compound is decomposed to produce related substances (relative retention time (RRT) by HPLC). The impurity at RRT 0.79 was an unknown related substance.

[0076] Naloxone HCl was also found to be unstable in PEG-based formulations. A 9.1% aqueous solution of naloxone HCl was prepared. 1.00 g of this 9.1% naloxone HCl was added. The Cl solution was combined with 4.70 g of PEG300 and 4.30 g of PEG1450. The PEG-based formulation was prepared by dissolving 10.00 g of this 0.91% naloxone HCl in water. The stability of this naloxone HCl formulation at room temperature was tested over a 2-month period. At 2 months, the growth of degradation products was observed as shown in Table 1 below. This is because naloxone HCl is unstable even in this PEG-based formulation. Deg 1 corresponds to the relative retention time of the unknown related substance mentioned above.

[0077] [Table 1]

[0078] B. Isolation and Identification of Naloxone N-Oxide The need to separate large amounts of PEG material to identify degradation products of interest The unknowns were then analyzed using multi-step liquid chromatography methods, which required considerable time and effort. Related substances were isolated. Approximately 200 g of 1% naloxone free base ointment in PEG 300 was The mixture was aged in a temperature chamber and used for isolation. Wash with 0.1% phosphoric acid and then elute with 40% methanol solution. 8 cartridges were used to concentrate degradation products of interest in formulation samples. The fractions were combined and lyophilized. Isolated by preparative HPLC using a preparative HPLC system Security Guard PREP C18 Cartridge (21.2 x 15 mm) ) equipped with a Phenomenex Luna C18 column (5 μm, 21.2 × 150 mm) was used.

[0079] 6.2 mM 1-octanesulfonic acid sodium saline with 0.1% phosphoric acid mobile phase 35% methanol in solution was used. The flow rate was 20 mL / min for an 18-minute isocratic run. The wavelength of the UV detector was 205 nm. The slope was 100 uV / sec and the Fractions were collected between 7 and 14 minutes when a level of 0.00 uV was observed. Re-analysis of the fractions showed that the related substances present in the fraction samples were greater than 99% pure. (Appendix A23). Ag run at isocratic 35% methanol in 6.2 mM water. ilent Zorbax Eclipse XDB-C18(5μm, 4.6×150 A 100 mm analytical column was used.

[0080] 1-octanesulfonic acid sodium salt with 0.1% phosphoric acid mobile phase for 15 min was used for analytical purity. A strong elution with methanol followed by 5% HCl in water The final impurity concentration is determined by using a cation exchange (SCX) cartridge to remove the buffer. The isolation was complete. The fractions containing the related substances were combined and the pH was adjusted to 7.0±0.5. The digest was extracted four times with equal volumes of a 3:1 solution of chloroform and isopropanol. The combined organic extracts were dried over sodium sulfate and concentrated to dryness. After the above purification, the purity of the isolated digest was reduced to 92%.

[0081] Once sufficient milligram quantities of degradation products have been isolated, they can be analyzed using mass spectrometry and NMR. High-resolution mass spectrometry data of the isolated digests was analyzed using Waters U Waters UPLC Xevo system controlled by NIFI software Acquired using a G2-XS QT Waters CORTECS UPLC S A 1.6 μm 3×50 mm column was used. Mobile phase A was water. The mobile phase A was 0.1% formic acid in acetonitrile. The flow rate was 0.2 mL / min. A gradient of 5% to 90% B in 5 min was applied. HRMS showed 5 The molecular formula was obtained as C19H21NO5 with a mass error of less than ppm.

[0082] NMR data were acquired on a Bruker 400 MHz spectrometer at ambient temperature. The values were reported in ppm relative to TMS. 1 H, 13 C, and 15 The nucleus of N was used NMR experiments and two-dimensional NMR experiments were performed. The observed signals in the NMR spectrum are consistent with the expected number and proportion of protons for the proposed structure. It matches the type of roton. 13 Analysis of the C NMR spectrum reveals that 18 of the 19 carbons Carbon assignments were made using available data from all NMR experiments. Obtained 15 The N NMR spectrum shows one nitrogen resonance at 129.2 ppm. It was observed that 15 The N shift supports the assignment of the proposed structure as an N-oxide. The NMR data show that the naloxone core structure is intact, with no protons or carbons It is confirmed that there is no loss of signal. Importantly, 21 protons, 5 CH carbon, and seven additional CH2 carbons were observed and identified from the mass spectral data. This indicates that oxygen is not attached to any carbon atom. Compared to naloxone, exchangeable protons, as well as the sigma assigned to H9, H16, H17, and H10. A significant downfield shift was observed for the null. showed a significant shift from 0.5 ppm (naloxone) to 129.2 ppm (degradants). These data showed significant changes in the electrons surrounding the nitrogen atom due to the impurity. The data concluded that the impurity was naloxone N-oxide. The related substances identified were directly compared by HPLC with a commercially available standard of naloxone N-oxide. The amount of naloxone N-oxide was first determined by a naloxone standard. It is then corrected for the response factor. The response factor for naloxone N-oxide is 1.19. do.

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

[0084] [ka]

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

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

[0087] In summary, formulations with the best stability can be obtained by the following essential approaches: can. 1. Use Croda's super refined PEG400 from an unopened container do 2. Run argon protection during the mixing process 3. Blow argon into the melted ointment before filling. 4. Use an argon blanket on the headspace of the tube or container to ensure the ointment Avoid contact with air

[0088] 1. Antioxidant-based formulations The preparation was carried out by first adding all ingredients except the PEG 1450 at room temperature and stirring. Then, PEG1450 was added and the mixture was stirred until all the PEG1450 was dissolved. Once a homogeneous mixture was formed, it was poured into a tube and placed in a ca. The mixture was poured into a glass and cooled to room temperature to form an opaque ointment. and / or citric acid were added to 1% PEG-based naloxone (NLX) ointment. Both PEG 300 and PEG 400 were examined for differences in stability over a 3-month period at 25°C. The results are shown in Table 2 below.

[0089] [Table 2-1]

[0090] [Table 2-2]

[0091] Some differences were observed between formulations, but these were due to the addition of antioxidants or the PEG used. None of the modifications stabilized the ointment to a sufficiently low (near zero) concentration of naloxone N-oxide. Additional studies of other formulations were performed at shorter time points. The results are shown in Table 3 below.

[0092] [Table 3]

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

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

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

[0096] [Table 4]

[0097] The percentage of naloxone N-oxide for each of these ointments is shown in Figure 1 and PEG300 or PEG400, shown in Figure 2, containing 12 ppm or less of peroxide. Ointments prepared from either 00 contain negligible pharmaceutically acceptable levels of naloxone. The results showed that the PEG prepared with low molecular weight PEG had higher levels of peroxides, whereas the results showed that the PEG prepared with low molecular weight PEG had higher levels of peroxides. Even the purified PEG400 obtained from DOW has become showed unacceptable growth of identified degradants.

[0098] Table 5 below shows the results of Croda super refined PEG 400 (1% AP 1% naltrexone salt prepared in PEG-1450 (60% PEG400, 39% PEG1450) Stability data for the base (w / w) formulation is shown. A response factor of 1.19 was used to determine the degradant naloxone. The levels of benzophenone N-oxide were calculated. For other unknown related substances, the response factor was 1. These data in the table below are based on these assays. This formulation, prepared using a peroxide PEG400 source and the method described above, was stored at 40°C / 7°C for 6 months. Based on 5% RH data, it has demonstrated acceptable stability for 2 years at room temperature. are.

[0099] [Table 5]

[0100] 3. Minimal effect of argon in processing and storage 1.0% naloxone free base (NLX) PEG-based ointment was prepared by argon injection into the melting ointment. Croda super with and without blown and tube blanketing Refined (low peroxide) PEG400 (60%) and PEG1450 (39%) ) was prepared using PEG400, which is not low in peroxide, and additional argon This same formulation was prepared using the same process. Accelerated stability testing at 40°C / 75% RH for 6 months was performed. In the study, the low peroxide PEG400 (SR) formulation, whether or not treated with argon, , showing low concentrations of degradant 1 (naloxone N-oxide) and higher peroxide PEG40 The 0 formulation showed higher concentrations of this degradant (see Table 6 below). For the PEG400(Hi) formulation of peroxide, at longer times, this effect was actually is partially obscured by the further decomposition of nicotine N-oxide to other decomposition products. It should be noted that the peroxide level of the PEG400 source has a significant effect, Lugon treatment does not result in any appreciable improvement in the degradation rate.

[0101] [Table 6]

[0102] E. Identification of Additional Impurities 1. Gradient Assay Method The HPLC method used in the previous study (the "old" method) coeluted with the N-oxide. Another impurity was suspected. A longer study was performed to provide quantification of this potentially new impurity. We developed a "new" gradient method with fast execution time. In addition, the "old" method was 100μ The sample concentration was 0.05 mg / mL, which allows for a larger limit of quantitation (LOQ) and limit of detection (L The "new" method involves increasing the sample concentration to 500 μg / mL. The LOQ of the "new" impurity method was approximately 0.03%, and the LOQ of the The OD is 0.02%. The "old" impurity method was also used as a comparative assay. The "new" method is used in the following examples.

[0103] [Table 7]

[0104] [Table 8]

[0105] 2. Effect of high molecular weight PEG Croda super re from two different manufacturers (Dow and BASF) Fined (low peroxide) PEG400 (60%) and PEG1450 (39%) were used. A 1.0% naloxone free base (NLX) PEG-based ointment was prepared using argon. Both ointments were prepared under running conditions. Table 9 shows the impurities in these five RRTs. Growth was consistently greater in DOW PEG 1450, especially when stored at 40°C. In other words, it is clear that BASF PEG1450 and Croda PE The G400 was much more stable.

[0106] [Table 9]

[0107] 3. Effect of antioxidants on formulations using BASF PEG1450 This same more stable formulation, namely BASF PEG with Croda PEG400, 1450 also contains selected antioxidants, BHT and PEG-1450, which are soluble in polyethylene glycol. and galactopropyl were added to prepare the solution.

[0108] In this series of experiments, the following changes were made: First, storage at 60°C was changed to storage at 40°C. The 40°C condition was replaced by storage at 40°C, which is a typical accelerated stability condition for this PEG ointment. This is because below 40°C the composition may contain both liquid and solid components, On the other hand, ointments are liquid at 40°C, meaning that they undergo a phase transition to a liquid, and even at 40°C, they are simply Storage at 60°C presents a more extreme challenge to stability than temperature excursions. Below 60°C, the ointment is completely degraded and can be considered the worst case scenario. It is entirely in liquid form. One month at 60°C is equivalent to about two years at 25°C. Temperature may allow for different degradation pathways, so some degradation may occur at 60°C. This may not occur at lower temperatures. Second, in this study, the assay was performed on the total ointment. Reported as %. Target API loading is 1%.

[0109] Antioxidants have been used in the past in formulations with Dow PEG, but the antioxidant The impurity concentration was too high in the Dow PEG formulation for which no effect was observed. a super-refined PEG400 and BASF PEG1450, The overall impurity levels are much lower compared to previous formulations. For PEG400 and BASF PEG1450, the use of selected antioxidants is beneficial. Tables 10 and 11 show the results of the analysis using antioxidants, 1% propyl gallate, and Croda PEG400 and BAS with and without 0.1% BHT. F PEG1450 formulations are compared. Lot 209-132-1 is BAS F Same as Lot 209-115-1 in Table 9 except contains PEG 1450 Specifically, the formulation containing 0.1% BHT in Table 10 showed a 0. Formulations that do not have more than 2% of any impurity, while containing 1% propyl gallate, also , and was found to be more stable than the same formulation without antioxidants.

[0110] [Table 10]

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

[0112] [Table 11]

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

[0114] [Table 12]

[0115] A third source with a molecular weight close to PEG 1450, JP Macrogol 1500R, is also available. Further investigation (Table 6) showed that antioxidants improved stability, and Dow PEG1 It was found to be better than 450 but not as good as BASF PEG1450.

[0116] [Table 13]

[0117] Additional examples using antioxidants are shown in the table below, with BHT and propyl gallate being the first. In addition to confirming the above-mentioned improvement results, the propyl gallate content was 0.1%. This same Croda PEG400 / BASF PEG1450 was compared with 0.05% propyl gallate and 0.1% BHT. Data was collected and the impurity level at RRT 0.81 after 3 months at 60°C was , and 0.05 and 0.06, respectively. Low levels such as 0.05% propyl gallate or 0.02% BHT combined Improved the stability of the ointment.

[0118] [Table 14]

[0119] [Table 15]

[0120] F. Efficacy of naloxone ointment in a rat model of atopic dermatitis pruritus by providing mice (HOS:HR-1 hairless) with a special chow diet. All groups were treated with a 3-week, 34-day, Each mouse was treated daily with 0.1 ml of ointment over its entire back. Video recording was performed for 30 minutes before administration (baseline activity) and after application. On days 45, 48, and 55, subjects were observed for scratching over a 1-hour period. The naloxone activator composition was allowed to dry for 1 hour before video recording of scratching behavior. Scratching behavior was monitored every 5 minutes for 1 hour, and the number of scratch bouts was counted as hind leg lift, back flexion, and back flexion. This may include one or more of the following behaviors: scratching inside or lowering the legs to the floor. The loading period was also determined. Also, days 34, 48, 55, and 20 (Phase 2) , and transepidermal water loss (TEWL) measured on days 33 and 55 (Phase 3). The treatment formulations according to group are shown in Table 16 below.

[0121] [Table 16]

[0122] Figure 3 shows the average scratch bouts and serotonin levels exhibited by mice on days 34 and 41. Figure 4 shows the cumulative scratch duration and the number of times the scratch was recorded. or 2) days 48 and 55 after applying a topical composition with naloxone free base. The average scratch bouts and cumulative scratch duration exhibited by the mice are shown in Fig. 1. Also, hydrophilic delivery vehicles containing polyethylene glycol or hydrophobic delivery vehicles The scratching behavior of mice to which the topical composition was applied was compared in the presence of a vehicle (petrolatum). Comparing.

[0123] Figure 5 shows the average scratch bouts and serotonin levels exhibited by mice on days 34 and 41. Figure 6 shows the cumulative scratch duration and the number of times the scratch was recorded. or 2) on days 48 and 55 after applying a topical composition with naloxone HCl The average scratch bouts and cumulative scratch duration exhibited by the mouse are shown. The results also show with a hydrophilic delivery vehicle containing polyethylene glycol, or with a hydrophobic delivery vehicle The scratching behavior of mice to which the topical composition was applied was compared in the presence of petrolatum. are.

[0124] As shown in Figures 3 to 6, the average scratch bout and cumulative scratch duration were Both can be reduced by topical delivery of either naloxone free base or naloxone HCl. In addition, the active agent naloxone and the hydrophilic delivery vehicle (polyethylene glycol) By applying a topical composition having only The product scratch duration was significantly reduced.

[0125] 7A-7C show placebo (no naloxone active agent) compositions and naloxone free base. Transdermal water retention was observed at 34, 48 and 55 days for topical compositions containing the As shown in Figures 7A-7C, compositions containing hydrophobic delivery vehicles showed a greater transepidermal water loss, which is due to the hydrophobic delivery system, such as petrolatum. This is not typical as the vehicle generally reduces water loss.

[0126] 8A-8B show placebo (no naloxone active agent) compositions and naloxone HCl. The transepidermal water loss shown at 33 and 55 days for topical compositions having Similar to compositions with naloxone free base, compositions containing a hydrophobic delivery vehicle Therefore, a composition containing only polyethylene glycol containing hydrophilic delivery vehicles showed greater transepidermal water loss than that shown by

[0127] 9A and 9B show placebo (no naloxone active agent) compositions and naloxone Example of mouse skin to which a topical composition having methacrylate free base and a hydrophobic delivery vehicle was applied. Figures 10A and 10B show representative photographs of the placebo (no naloxone active agent) formulation. and polyethylene glycol containing naloxone HCl and a hydrophilic delivery vehicle. 9A and 9B show exemplary photographs of mouse skin to which a topical composition having only acetone was applied. 9B with FIGS. 10A and 10B, the results show that the hydrophilic delivery vehicle alone Irritation and redness caused by scratching the skin of mouse subjects to which the composition was applied and less damage is demonstrated.

[0128] All tested topical naloxone compositions were effective in reducing pruritus in the hairless mouse model. Compared with the placebo group, the naloxone base + PEG (days 41 and 55) naloxone base + Shea XP (days 48 and 55) and naloxone base + Shea XP (days 48 and 55) A significant reduction in urinary tract obstruction was observed in the naloxone HCl + PEG (3 Days 4 and 55) and Naloxone HCl + Shea XP (Days 34, 41) A significant reduction in scratching behavior was observed in the 48th, 49th, and 55th days. Transepidermal water loss was measured using PEG-prepared naloxones containing either naloxone base or naloxone HCl. The Shea XP-containing formulation was significantly higher than the non-Shea XP-containing formulation.

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

[0130] The following claims, as generally defined herein and in particular in the appended claims (e.g., The terms used in this section of the text are generally intended as "open" terms ( For example, the term "including" means "including, but not limited to" "including but not limited to" and the term "having" should be interpreted as " The term "includes" should be interpreted as "having at least" should be interpreted as "including but not limited to," etc.) by a person skilled in the art. It is understood that where a particular number of introduced claim recitations is intended, such intention is expressly construed as a prerequisite for the invention. The invention is expressly recited in the patent claims, and in the absence of such recitation, no such intention exists. It will be further understood by those skilled in the art that the present invention is not limited to the above. The claims of this patent contain the introductory phrases "at least one" and "at least one" to introduce the claim. However, the same patent claim may contain "one or more" or The introductory phrase "at least one" and the use of "a" or "an" Even if a phrase contains an indefinite article such as "," the use of such a phrase is The introduction of a claim by "an" does not affect any claim that includes such an introduced claim. is meant to limit a particular claim to an embodiment containing only one such recitation. should not be construed as meaning "at least" (e.g., "a" and / or "an" should not be construed as meaning "at least"). (The term "one" should be interpreted to mean "one or more"), The same is true for the use of definite articles used to insert specific numbers. Even if the claims explicitly include the following, a person skilled in the art would recognize that such a sequence Recognize that a list should be interpreted to mean at least the number listed (e.g., other A bare enumeration of "two enumerations" without the modifier "two enumerations" is at least two enumerations, or two (This means an enumeration of the above.) Furthermore, "at least one of A, B, and C, etc." Where similar conventions are used, such syntax will generally be consistent with those of ordinary skill in the art who understand the conventions. (e.g., "having at least one of A, B, and C" The "system" includes, but is not limited to, A alone, B alone, C alone, both A and B, and A and C, B and C, and / or A, B, and C, etc. (This includes systems that do this.) Similar to "at least one of A, B, or C, etc." Where conventions are used, such syntax generally implies that one of ordinary skill in the art would understand the convention. intended in taste (e.g., "a system having at least one of A, B, or C" " includes, but is not limited to, A alone, B alone, C alone, A and B together, A and C A system with both, B and C together, and / or A, B, and C together, etc. Whether in the specification, claims, or drawings, two or more alternatives Virtually any disjunctive word and / or disjunctive phrase that presents a substitute term may be used to replace one of the terms. It should be understood by those skilled in the art that the term "common" should be understood to mean the possibility of including either or both terms. For example, the phrase "A or B" means either "A" or "B." or "A and B" possibilities.

[0131] Furthermore, when a feature or aspect of the disclosure is described in terms of a Markush group: Those skilled in the art will appreciate that the present disclosure thereby provides a method for identifying any individual member of the Markush group. or any subgroup of members of the Markush group. Recognize that.

[0132] As will be appreciated by those skilled in the art, any and all purposes, including providing a written description, For the purposes of clarity, all ranges disclosed herein also include any and all possible subranges. Any listed range includes the same range. decomposes into at least equal halves, thirds, quarters, fifths, tenths, etc. The structure is easily recognizable as being sufficiently representative to allow it to be disassembled. As a non-limiting example, each range discussed herein can easily be divided into the lower third, middle third, As will be understood by those skilled in the art, the above-mentioned embodiment may be broken down into a top third, a bottom third, a bottom third, etc. All terms such as "maximum," "at least," "greater than," and "less than" are , refers to a range that is inclusive of the recited numbers and that may be subsequently broken down into subranges as described above. As will be understood by one of ordinary skill in the art, a range includes each individual member. A group having three items refers to a group having one, two, or three items. A group having up to 5 items refers to a group having 1, 2, 3, 4, or 5 items. and so on.

[0133] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, Those skilled in the art will recognize that, in light of the teachings of the present invention, It will be readily apparent that certain changes and modifications can be made without departing from the scope of the invention.

[0134] Accordingly, the foregoing merely illustrates the principles of the invention. Although not explicitly described or shown herein, the present invention embodies the principles of the present invention and It will be understood that various modifications may be devised which fall within the spirit and scope of the present invention. All examples and conditional terms listed in the specification are intended primarily to help the reader understand the principles of the present invention and and understanding of the concepts provided by the inventors to further the art. is intended to be helpful and is not limited to such specifically listed examples and conditions. Furthermore, the principles, aspects, and embodiments of the present invention are enumerated. All statements herein, and specific examples thereof, are intended to encompass structural and functional equivalents thereof. Additionally, such equivalents are intended to encompass both the present invention and the related art, regardless of structure. This includes both currently known equivalents and future equivalents, i.e., equivalents that perform the same function. It is intended to include any element developed to Any disclosure of the invention is not expressly recited in the claims. Whether or not it is, it is not intended to be publicly dedicated.

[0135] The scope of the present invention, therefore, is not limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is defined by the appended claims. The claims are embodied in the claims. ) or 35 U.S.C. § 112(6) provides that "means for" or The exact phrase "step for" appears in the patent claim. A limitation in a claim may be invoked only when it is recited at the beginning of the limitation. and such exact phrases are clearly defined as being in the patent claims. § 112(f) also applies to the invention if it is not used in a limitation within the (6) also does not apply.

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

Claims

1. A storage-stable non-aqueous topical composition comprising naloxone free base and a non-aqueous vehicle comprising a first polyethylene glycol having an average molecular weight of 600 g / mol or less and a second polyethylene glycol having an average molecular weight of 1000 g / mol or more, The composition does not contain naloxone N-oxide and is formulated to deliver naloxone through the skin surface of a subject.

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

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

4. 10. The storage-stable, non-aqueous topical composition of claim 1, wherein the second polyethylene glycol has an average molecular weight of 1350 g / mol or greater.

5. 10. The storage-stable, non-aqueous topical composition of claim 1, wherein the first polyethylene glycol has an average molecular weight of 300 to 400 g / mol.

6. 6. The storage-stable, non-aqueous topical composition of claim 5, wherein the second polyethylene glycol has an average molecular weight of 1400 to 1500 g / mol.

7. A storage-stable non-aqueous topical composition as described in claim 6, comprising 20 to 90% by weight of the first polyethylene glycol.

8. 8. The storage-stable, non-aqueous topical composition of claim 7, comprising a greater amount by weight of said first polyethylene glycol than said second polyethylene glycol.

9. A storage-stable non-aqueous topical composition as described in claim 8, comprising 20 to 50% by weight of the second polyethylene glycol.

10. The storage-stable non-aqueous topical composition of claim 1, comprising 1% by weight of naloxone free base, 20-90% by weight of a first polyethylene glycol (wherein the first polyethylene glycol has an average molecular weight of 300 g / mol to 400 g / mol), and 20-50% by weight of a second polyethylene glycol (wherein the second polyethylene glycol has an average molecular weight of 1400 g / mol to 1500 g / mol).

11. A storage-stable non-aqueous topical composition as described in claim 1, wherein at the time the composition is prepared, at least the first polyethylene glycol component contains 20 ppm or less of peroxide.

12. 10. The storage-stable, non-aqueous topical composition of claim 1, substantially free of one or more additional impurities.

13. 13. The storage-stable non-aqueous topical composition of claim 12, wherein the one or more additional impurities are selected from the group consisting of RRT 0.32, RRT 0.43, RRT 0.82, RRT 0.86, and RRT 2.

63.

14. The storage-stable, non-aqueous topical composition of claim 1, further comprising one or more antioxidants.

15. 15. The storage-stable, non-aqueous topical composition of claim 14, wherein the one or more antioxidants are present in an amount ranging from 0.01 to 5.0% w / w.

16. 15. The storage-stable, non-aqueous topical composition of claim 14, wherein the one or more antioxidants are selected from the group consisting of BHT and propyl gallate.

17. The storage-stable non-aqueous topical composition of claim 1, comprising 1 wt. % naloxone free base, 20-90 wt. % of a first polyethylene glycol (wherein the first polyethylene glycol has an average molecular weight of 300 g / mol to 400 g / mol), 20-50 wt. % of a second polyethylene glycol (wherein the second polyethylene glycol has an average molecular weight of 1400 g / mol to 1500 g / mol), and 0.02-2.0 wt. % BHT.

18. 10. The storage-stable, non-aqueous topical composition of claim 1, formulated to deliver the naloxone free base locally.

19. 10. The storage-stable, non-aqueous topical composition of claim 1, formulated to deliver the naloxone free base locally for 2 to 7 hours after application.

20. 10. The storage-stable, non-aqueous topical composition of claim 1, which is a cream, gel, lotion, or ointment.

21. 21. The storage-stable, non-aqueous topical composition of claim 20, wherein the composition is an ointment.

22. A storage-stable, non-aqueous topical composition according to any one of claims 1 to 21 for use in application to the skin of a subject in need thereof.

23. A storage-stable non-aqueous topical composition according to any one of claims 1 to 21 for use in the treatment and prevention of inflammatory skin diseases in a subject in need thereof.

24. 24. The storage-stable non-aqueous topical composition for use according to claim 23, wherein the inflammatory skin disease is selected from the group consisting of atopic dermatitis, eczema, psoriasis, and combinations thereof.

25. A storage-stable, non-aqueous topical composition according to any one of claims 1 to 21 for use in the treatment and prevention of non-inflammatory skin diseases in a subject in need thereof.

26. 26. The storage-stable non-aqueous topical composition for use according to claim 25, wherein the non-inflammatory skin disease is chronic prurigo.

27. A storage-stable, non-aqueous topical composition according to any one of claims 1 to 21 for use in the treatment and prevention of pruritus in a subject in need thereof.

28. 28. The storage-stable, non-aqueous topical composition for use according to claim 27, wherein the pruritus is associated with one or more of an inflammatory skin disease, a non-inflammatory skin disease, primary biliary cirrhosis, chronic renal failure, kidney dialysis, abnormal blood pressure, thyroid dysfunction, aging, cancer, anemia, parasites, a neurological condition, or pregnancy.

29. 29. The storage-stable non-aqueous topical composition for use according to claim 28, wherein the pruritus is drug-induced pruritus or pruritogen-induced pruritus.

30. 30. The storage-stable, non-aqueous topical composition for use according to any one of claims 22 to 29, wherein the composition is formulated to treat or prevent itching associated with a skin condition.

31. 30. The storage-stable, non-aqueous topical composition for use according to any one of claims 22 to 29, wherein the topical composition is applied directly to the locus of the skin condition.

32. 32. The storage-stable, non-aqueous topical composition for use according to claim 31, wherein the topical composition is applied to the skin of the subject in a manner sufficient to cover the entire skin condition.

33. 30. The storage-stable, non-aqueous topical composition for use according to any one of claims 22 to 29, wherein the topical composition is maintained in contact with the skin of the subject for one hour or more.

34. 30. The storage-stable, non-aqueous topical composition for use according to any one of claims 22 to 29, wherein the topical composition is maintained in contact with the skin of the subject for 2 to 7 hours.

Images