A stable form of capsaicin palmitate for pain treatment.

Abstract

To provide a pharmaceutical composition comprising a solid form of capsaicin palmitate, useful for the treatment of pain, and a preparation thereof. [Solution] Disclosed herein is a compound of formula (I) in solid form: TIFF2026077618000044.tif37128 The solid form comprises the solvate, hydrate, or isotope thereof, and is characterized by an X-ray powder diffraction pattern having at least one peak position selected from 5.48, 13.74, 19.22, and 20.06 at a degree 2θ (±0.2°). Related pharmaceutical compositions and therapeutic methods are also disclosed herein.

Description

[Technical Field]

[0001] This disclosure relates to pharmaceutical compositions, including solid forms of capsaicin palmitate and formulations thereof, which are useful for the treatment of pain. The compositions disclosed herein include well-tolerated, non-burning capsaicin analgesics for the treatment of mild to moderate pain, exhibiting few recognizable side effects. Palmitoylated formulations of capsaicin have analgesic efficacy but produce a unique solid form with reduced heat sensitivity compared to capsaicin palmitate synthesized using previously described methods. [Background technology]

[0002] Pain management therapies are limited. Chronic pain is a debilitating condition affecting an estimated 50 million adults, or about 20% of the adult population, in the United States, according to the National Institutes of Health (NIH). Over-the-counter (OTC) analgesics may be useful in treating mild to moderate pain, but like all medications, they have limitations and risks.

[0003] Analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs), which are "black-boxed" by the FDA as a drug category, including diclofenac, which has potential cardiovascular toxicity, present problems. NSAIDs may be effective in treating mild to moderate pain. However, they may not be effective for more severe or chronic pain conditions. Analgesics, particularly NSAIDs and acetaminophen, can have a wide range of side effects, including gastrointestinal problems (e.g., ulcers and bleeding), liver damage, and kidney damage, which can result from frequent use. These risks may increase if the drug is taken in high doses or over a long period of time. Such drugs may interact with other drugs, may be dangerous if taken in excessive doses (leading to overdose and potentially life-threatening complications), and their range of treatment options may be limited, and they may not be effective for all types of pain, such as neuropathic pain.

[0004] Topical analgesics can be successfully used to relieve mild to moderate pain in areas of the body, such as bruises, sprains, or injured muscles or joints. However, pain management with topical analgesics is associated with various pharmacologic challenges, including limited efficacy and skin tolerability compared to other routes of administration. For example, topical analgesics can cause skin irritation, especially with prolonged use. Common adverse effects include erythema or contact dermatitis, burning or itching, photosensitivity, dryness, or skin discoloration. Topical analgesics may not be absorbed into the bloodstream as effectively as oral medications, which can limit their effectiveness for certain types of pain. Topical creams and gels are generally perceived as safe by patients, which can lead to the possibility of overdose. While topical analgesics are generally safe, they can be dangerous when applied in high doses, used for extended periods, or ingested.

[0005] Despite the large number and variety of options available, over-the-counter (OTC) topical medications have therapeutic limitations. While topical medications fall within a spectrum of drugs recognized by physicians as moderately effective, they are generally available in a narrow range of concentrations. Examples include monotherapy drugs such as capsaicin, NSAIDs, methyl salicylate, menthol, and camphor. The limited dosage range for OTC topical medications stems from the difficulty in achieving concentrations that are effective but do not cause harmful side effects.

[0006] Therefore, most topical analgesics are not well-suited for treating severe pain caused by nerve damage, postoperative or traumatic pain, or chronic pain resulting from conditions such as arthritis or cancer. Complicating the general inadequacy of pain relief due to the limited concentration of topical medications is the associated problem of adverse skin characteristics. To avoid drug side effects, topical therapy is generally limited to treating mild to moderate pain, such as pain in the early stages of arthritis or pain found in bruises and sprains. Robert L Barkin, "The pharmacology of topical analgesics", Postgrad Med.2013,125(4 Suppl 1):7-18 PMID:24547599doi:10.1080 / 00325481.2013.1110566911, Frias B, Merighi A. Capsaicin, Nociception and Pain.Molecules.2016 Jun 18;21(6):797.PMID:27322240 doi:10.3390 / molecules21060797, Basbaum, AI, Bautista, DM, Scherrer, G., & Julius, D. “Cellular and molecular mechanisms of pain”,Cell,2009,139(2),267-284 PMID:19837031 See doi:10.1016 / j.cell.2009.09.028.

[0007] The purpose of this disclosure was to address these issues through the discovery of a unique solid form of a known capsaicin derivative, capsaicin palmitate (also referred to herein as "CP"). Capsaicin was selected as the study molecule due to its analgesic properties. Bioavailability was enhanced by increasing the lipophilicity of capsaicin using esterification with palmitic acid. The use of capsaicin is not ideal because its topical analgesic capacity is limited by its concentration due to its low epidermal absorption and tendency to cause thermal irritation of the skin. It has been well established that such thermal irritation to the skin can reduce patient adherence and thereby limit the applicability of the treatment. Generally, the focus of using palmitoylation in topical products such as lotions and creams has been to increase absorption. Palmitoylation is also advantageous due to its ability to resist enzymatic degradation of the ester bond, thereby increasing the half-life of the palmitic acid derivative in both tissue and bloodstream. Natural capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, C 18 H 27NO3) is a capsaicinamide composed of congeners with different hydrophobic chain ends (Wei Zhang et al., Pharmacological activity of capsaicin: Mechanisms and controversies (Review). Mol Med Rep. 2024 Mar;29(3):38. https: / / doi.org / 10.3892 / mmr.2024.13162). More prominent congeners relative to capsaicin include dihydrocapsaicin (30-40%), nordihydrocapsaicin (<10%), dihydrohomocapsaicin, and homocapsaicin (combined <5%). The phenolic hydroxyl group is present in each of these congeners at the para position of the phenylene group (relative to the aminoalkyl group) and is a nucleophilic group for ester formation, such as those produced with palmitic acid. Therefore, when the present invention refers to capsaicin and its palmitate capsaicin esters, it is assumed that the naturally occurring families of dihydrocapsaicin, nordihydrocapsaicin, dihydrohomocapsaicin, homocapsaicin, and palmitate dihydrocapsaicin, palmitate nordihydrocapsaicin, palmitate dihydrohomocapsaicin, and palmitate homocapsaicin are included as a whole. PCT / US2024 / 030982 (the entire contents of which are incorporated herein by reference) discloses a solid form of CP discovered in a controlled clinical thermosensitivity study designed to identify a non-irritating, non-flammable form of CP. As a comparative form of CP (also referred herein as “Form T”), known CP was also prepared using the method disclosed in U.S. Patent No. 7,943,666(B2) (the entire contents of which are incorporated herein by reference). The methodology proposed in the '666 patent describes a method for synthesizing one form of CP, where the addition of a myristic acid ester to CP (claim 1 of U.S. Patent No. 7,943,666) is claimed as a further therapeutic component not required in this disclosure of a unique form of CP. The crystalline form of CP in this disclosure (also referred herein as “Form C”, or “CP Form C”) was discovered during discrete variable temperature melting based on unique endothermic properties found by differential scanning calorimetry (DSC). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] US Patent No. 7,943,666(B2) [Non-patent literature]

[0009] [Non-Patent Document 1] Robert L Barkin, "The pharmacology of topical analgesics", Postgrad Med.2013,125(4 Suppl 1):7-18 PMID:24547599doi:10.1080 / 00325481.2013.1110566911 [Non-Patent Document 2] Frias B,Merighi A.Capsaicin,Nociception and Pain.Molecules.2016 Jun 18;21(6):797.PMID:27322240 doi:10.3390 / molecules21060797 [Non-Patent Document 3] Basbaum, AI, Bautista, DM, Scherrer, G., & Julius, D. "Cellular and molecular mechanisms of pain", Cell, 2009, 139(2), 267-284 PMID:19837031 doi:10.1016 / j.cell.2009.09.028 [Non-Patent Document 4] Wei Zhang et al.,Pharmacological activity of capsaicin:Mechanisms and controversies(Review).Mol Med Rep.2024 Mar;29(3):38.https: / / doi.org / 10.3892 / mmr.2024.13162 [Overview of the Initiative]

[0010] In one embodiment, the present disclosure relates to a compound of formula (I) in solid form (referred to herein as “Form C” or “CP Form C”):

[0011] [ka] Alternatively, the invention provides a solvate, hydrate, or isotope thereof, the solid form characterized by an X-ray diffraction pattern having at least one peak position selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°).

[0012] In another embodiment, the Disclosure provides a pharmaceutical composition comprising the solid form of the Disclosure and at least one selected from the group consisting of antioxidants, emollients, emulsifiers, humectants, preservatives, and surfactants.

[0013] In another embodiment, the present disclosure provides a method for treating a disease, comprising administering an effective amount of the solid form of the present disclosure to a subject in need thereof, or by administering an effective amount of the pharmaceutical composition of the present disclosure to a subject thereof.

[0014] In another aspect, the treatment method of the present disclosure further comprises administering to the subject an additional therapeutic agent, a secondary therapy, or a combination thereof. In one embodiment, for example, the following items are provided. (Item 1A) A solid form of capsaicin palmitate, which is a compound of formula (I): [Chemical formula] Or a solvate, hydrate, or isotope thereof, wherein the solid form is characterized by an X-ray diffraction pattern comprising at least one peak position selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at degree 2θ (±0.2°). (Item 2A) The solid form according to the preceding item, wherein the X-ray diffraction pattern comprises at least two peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at degree 2θ (±0.2°). (Item 3A) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern comprises at least three peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at degree 2θ (±0.2°). (Item 4A) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern comprises peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at degree 2θ (±0.2°). (Item 5A) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern comprises the peak positions of 5.48, 13.74, 19.22, and 20.06 at degree 2θ (±0.2°), and at least one peak position selected from the group consisting of 8.24, 14.65, 15.80, and 18.30. (Item 6A) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern includes peak positions of 5.48, 13.74, 19.22, and 20.06 at degrees 2θ (±0.2°), and at least two peak positions selected from the group consisting of 8.24, 14.65, 15.80, and 18.30. (Item 7A) The solid form described in any one of the preceding items, wherein the X-ray diffraction pattern includes a peak position selected from the group consisting of 5.48, 8.24, 13.74, 14.65, 15.80, 18.30, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 8A) A solid form according to any one of the preceding items, further comprising at least one palmitate ester formed from a congener of capsaicin. (Item 9A) Compound of formula (II): [ka] Or a solid form according to any one of the preceding items, further comprising a solvate, hydrate, or isotope thereof. (Item 10A) A pharmaceutical composition, The solid form described in any one of the preceding items, A pharmaceutical composition comprising at least one selected from the group consisting of antioxidants, emollients, emulsifiers, humectants, preservatives, and surfactants. (Item 11A) A pharmaceutical composition according to any one of the preceding items, comprising at least one antioxidant. (Item 12A) A pharmaceutical composition according to any one of the preceding items, comprising at least one emollient agent. (Item 13A) A pharmaceutical composition according to any one of the preceding items, comprising at least one emulsifier. (Item 14A) A pharmaceutical composition according to any one of the preceding items, comprising at least one humectant. (Item 15A) A pharmaceutical composition according to any one of the preceding items, comprising at least one preservative. (Item 16A) A pharmaceutical composition according to any one of the preceding items, comprising at least one surfactant. (Item 17A) A pharmaceutical composition according to any one of the preceding items, comprising at least one selected from the group consisting of vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester), Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, Ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil. (Item 18A) A pharmaceutical composition according to any one of the preceding items, comprising vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester) or Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil. (Item 19A) A method for treating pain from a disease in a subject in need thereof, comprising administering to the subject an effective amount of a solid form described in any one of the preceding items. (Item 20A) A method for treating pain from a disease in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition described in any one of the preceding items. (Item 21A) The method according to the preceding item, wherein the disease is selected from the group consisting of postherpetic neuralgia, diabetic neuropathy, neuropathy, metatarsalgia, or diabetic foot pain due to gout, hallux valgus, hyperemesis gravidarum syndrome due to cannabis or cannabinoids, postmastectomy pain syndrome, oral neuropathy pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders including synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain due to hip and vertebral disorders such as hernias, fibromyalgia, cluster headaches, dermatitis, contact dermatitis, skin diseases such as Stevens-Johnson syndrome, skin diseases, skin conditions, pain and itching from other inflammatory lesions such as erythema, or combinations thereof. (Item 22A) The method according to any one of the preceding items, wherein the disease is selected from the group consisting of postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, joint pain of the neck, hand or fingers, stenotic synovitis, dystrophy of the knee, hip, ankle or wrist, carpal tunnel syndrome, nasal lesions, oral mucositis, skin allergy, hyperdetrusor reflex, pain due to anticancer chemotherapy, sporadic pain / hematuria syndrome, cervical disorders, pain due to multiple sclerosis, stump pain, reflex sympathetic dystrophy, complex regional pain syndrome (Type II; burning), allodynia, idiopathic pain, pain due to skin tumors, pain due to spinal cord injury, pain due to foot injury, pain due to fracture, pain due to dislocation, and combinations thereof. (Item 23A) The method according to any one of the preceding items, wherein the administration is via local, oral, injection, or electrophoretic application. (Item 24A) The method according to any one of the preceding items, further comprising administering an additional therapeutic agent, a second-line therapy, or a combination thereof to the subject. (Item 25A) The method according to any one of the preceding items, further comprising administering radiotherapy, surgical therapy, immunotherapy, gene therapy, chemotherapeutic agents, nonsteroidal anti-inflammatory drugs, and combinations thereof to the subject. In another embodiment, for example, the following items are provided: (Item 1B) A solid form of capsaicin palmitate, which is a compound of formula (I): [ka] Alternatively, a solid form comprising a solvate, hydrate, or isotope thereof, wherein the solid form is characterized by an X-ray diffraction pattern having at least one peak position selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 2B) The solid morphology described in the preceding item, wherein the X-ray diffraction pattern includes at least two peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 3B) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern includes at least three peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 4B) The solid form described in any one of the preceding items, wherein the X-ray diffraction pattern includes a peak position selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 5B) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern includes peak positions of 5.48, 13.74, 19.22, and 20.06 at degrees 2θ (±0.2°), and at least one peak position selected from the group consisting of 8.24, 14.65, 15.80, and 18.30. (Item 6B) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern includes peak positions of 5.48, 13.74, 19.22, and 20.06 at degrees 2θ (±0.2°), and at least two peak positions selected from the group consisting of 8.24, 14.65, 15.80, and 18.30. (Item 7B) The solid form described in any one of the preceding items, wherein the X-ray diffraction pattern includes peak positions selected from the group consisting of 5.48, 8.24, 13.74, 14.65, 15.80, 18.30, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 8B) A solid form according to any one of the preceding items, further comprising at least one palmitate ester formed from a congener of capsaicin. (Item 9B) Compound of formula (II): [ka] Or a solid form according to any one of the preceding items, further comprising a solvate, hydrate, or isotope thereof. (Item 10B) A pharmaceutical composition, The solid form described in any one of the preceding items, A pharmaceutical composition comprising at least one selected from the group consisting of antioxidants, emollients, emulsifiers, humectants, preservatives, and surfactants. (Item 11B) A pharmaceutical composition according to any one of the preceding items, comprising at least one antioxidant. (Item 12B) A pharmaceutical composition according to any one of the preceding items, comprising at least one emollient agent. (Item 13B) A pharmaceutical composition according to any one of the preceding items, comprising at least one emulsifier. (Item 14B) A pharmaceutical composition according to any one of the preceding items, comprising at least one humectant. (Item 15B) A pharmaceutical composition according to any one of the preceding items, comprising at least one preservative. (Item 16B) A pharmaceutical composition according to any one of the preceding items, comprising at least one surfactant. (Item 17B) A pharmaceutical composition according to any one of the preceding items, comprising at least one selected from the group consisting of vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester), Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, Ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil. (Item 18B) A pharmaceutical composition according to any one of the preceding items, comprising vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester) or Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil. (Item 19B) A method for treating pain from a disease in a subject in need thereof, comprising administering to the subject an effective amount of a solid form described in any one of the preceding items. (Item 20B) A method for treating pain from a disease in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition described in any one of the preceding items. (Item 21B) The method according to the preceding item, wherein the disease is selected from the group consisting of postherpetic neuralgia, diabetic neuropathy, diabetic foot pain due to neuropathy, metatarsalgia, gout, hallux valgus, hyperemesis gravidarum syndrome due to cannabis or cannabinoids, postmastectomy pain syndrome, oral neuropathy pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders, synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain due to hip and vertebral disorders, hernia, fibromyalgia, cluster headache, skin diseases, contact dermatitis, Stevens-Johnson syndrome, pain and itching from other inflammatory foci due to skin diseases, skin conditions, erythema, and combinations thereof. (Item 22B) The method according to any one of the preceding items, wherein the disease is selected from the group consisting of postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, joint pain of the neck, hand or fingers, stenotic synovitis, dystrophy of the knee, hip, ankle or wrist, carpal tunnel syndrome, nasal lesions, oral mucositis, skin allergy, hyperdetrusor reflex, pain due to anticancer chemotherapy, sporadic pain / hematuria syndrome, cervical disorders, pain due to multiple sclerosis, stump pain, reflex sympathetic dystrophy, complex regional pain syndrome (Type II; burning), allodynia, idiopathic pain, pain due to skin tumors, pain due to spinal cord injury, pain due to foot injury, pain due to fracture, pain due to dislocation, and combinations thereof. (Item 23B) The method according to any one of the preceding items, wherein the administration is via local, oral, injection, or electrophoretic application. (Item 24B) The method according to any one of the preceding items, further comprising administering an additional therapeutic agent, a second-line therapy, or a combination thereof to the subject. (Item 25B) The method according to any one of the preceding items, further comprising administering radiotherapy, surgical therapy, immunotherapy, gene therapy, chemotherapeutic agents, nonsteroidal anti-inflammatory drugs, and combinations thereof to the subject. (Item 26B) The method according to any one of the preceding items, wherein the disease is selected from the group consisting of postherpetic neuralgia, diabetic neuropathy, diabetic foot pain due to neuropathy, metatarsalgia, gout, hallux valgus, hyperemesis gravidarum syndrome due to cannabis or cannabinoids, postmastectomy pain syndrome, oral neuropathy pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders, synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain due to hip and vertebral disorders, hernia, fibromyalgia, cluster headache, skin diseases, contact dermatitis, Stevens-Johnson syndrome, pain and itching from other inflammatory foci due to skin diseases, skin conditions, erythema, and combinations thereof. (Item 27B) The method according to any one of the preceding items, wherein the disease is selected from the group consisting of postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, joint pain of the neck, hand or fingers, stenotic synovitis, dystrophy of the knee, hip, ankle or wrist, carpal tunnel syndrome, nasal lesions, oral mucositis, skin allergy, hyperdetrusor reflex, pain due to anticancer chemotherapy, sporadic pain / hematuria syndrome, cervical disorders, pain due to multiple sclerosis, stump pain, reflex sympathetic dystrophy, complex regional pain syndrome (Type II; burning), allodynia, idiopathic pain, pain due to skin tumors, pain due to spinal cord injury, pain due to foot injury, pain due to fracture, pain due to dislocation, and combinations thereof. (Item 28B) The method according to any one of the preceding items, wherein the administration is via local, oral, injection, or electrophoretic application. (Item 29B) The method according to any one of the preceding items, further comprising administering an additional therapeutic agent, a second-line therapy, or a combination thereof to the subject. (Item 30B) The method according to any one of the preceding items, further comprising administering radiotherapy, surgical therapy, immunotherapy, gene therapy, chemotherapeutic agents, nonsteroidal anti-inflammatory drugs, and combinations thereof to the subject. In a further embodiment, for example, the following items are provided: (Item 1C) A solid form of capsaicin palmitate, which is a compound of formula (I): [ka] Alternatively, a solid form comprising a solvate, hydrate, or isotope thereof, wherein the solid form is characterized by an X-ray diffraction pattern having at least one peak position selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 2C) The solid morphology described in the preceding item, wherein the X-ray diffraction pattern includes at least two peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 3C) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern includes at least three peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 4C) The solid form described in any one of the preceding items, wherein the X-ray diffraction pattern includes a peak position selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 5C) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern includes peak positions of 5.48, 13.74, 19.22, and 20.06 at degrees 2θ (±0.2°), and at least one peak position selected from the group consisting of 8.24, 14.65, 15.80, and 18.30. (Item 6C) The solid form according to any one of the preceding items, wherein the X-ray diffraction pattern includes peak positions of 5.48, 13.74, 19.22, and 20.06 at degrees 2θ (±0.2°), and at least two peak positions selected from the group consisting of 8.24, 14.65, 15.80, and 18.30. (Item 7C) The solid form described in any one of the preceding items, wherein the X-ray diffraction pattern includes peak positions selected from the group consisting of 5.48, 8.24, 13.74, 14.65, 15.80, 18.30, 19.22, and 20.06 at a degree of 2θ (±0.2°). (Item 8C) A solid form according to any one of the preceding items, further comprising at least one palmitate ester formed from a congener of capsaicin. (Item 9C) Compound of formula (II): [ka] Or a solid form according to any one of the preceding items, further comprising a solvate, hydrate, or isotope thereof. (Item 10C) A pharmaceutical composition, The solid form described in any one of the preceding items, A pharmaceutical composition comprising at least one selected from the group consisting of antioxidants, emollients, emulsifiers, humectants, preservatives, and surfactants. (Item 11C) A pharmaceutical composition as described in a preceding item, comprising at least one antioxidant. (Item 12C) A pharmaceutical composition according to any one of the preceding items, comprising at least one emollient agent. (Item 13C) A pharmaceutical composition according to any one of the preceding items, comprising at least one emulsifier. (Item 14C) A pharmaceutical composition according to any one of the preceding items, comprising at least one humectant. (Item 15C) A pharmaceutical composition according to any one of the preceding items, comprising at least one preservative. (Item 16C) A pharmaceutical composition according to any one of the preceding items, comprising at least one surfactant. (Item 17C) A pharmaceutical composition according to any one of the preceding items, comprising at least one selected from the group consisting of vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester), Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, Ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil. (Item 18C) A pharmaceutical composition according to any one of the preceding items, comprising vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester) or Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil. (Item 19C) A composition comprising a solid form as described in any one of the preceding items, for treating pain from a disease in a person in need thereof. (Item 20C) A pharmaceutical composition according to any one of the preceding items, for treating pain from a disease in a person in need thereof. (Item 21C) The composition according to any one of the preceding items, wherein the disease is selected from the group consisting of postherpetic neuralgia, diabetic neuropathy, diabetic foot pain due to neuropathy, metatarsalgia, gout, hallux valgus, metatarsalgia, Morton's neuroma, hyperemesis gravidarum syndrome due to cannabis or cannabinoids, postmastectomy pain syndrome, oral neuropathy pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders, synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain due to hip and vertebral disorders, hernia, fibromyalgia, cluster headache, skin diseases, contact dermatitis, Stevens-Johnson syndrome, pain and itching from other inflammatory foci due to skin diseases, skin conditions, erythema, endometriosis, migraine, sciatica, frozen shoulder, vascular occlusive pain due to sickle cell anemia, interstitial cystitis, and combinations thereof. (Item 22C) The aforementioned diseases include postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, phantom limb pain, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, tension headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, joint pain of the neck, hand or fingers, stenotic synovitis, dystrophy of the knee, hip, ankle or wrist, carpal tunnel syndrome, nasal lesions, oral mucositis, skin allergies, hyperdetrusor reflex, and those caused by anticancer chemotherapy. Pain, isolated pain / hematuria syndrome, cervical pain, pain due to multiple sclerosis, stump pain, reflex sympathetic dystrophy, complex regional pain syndrome (CRPS) type I (formerly known as reflex sympathetic dystrophy), complex regional pain syndrome (type II; burning pain), allodynia, idiopathic pain, pain due to skin tumors, pain due to spinal cord injury, pain due to foot injury, pain due to fracture, pain due to dislocation, myofascial pain syndrome, systemic lupus erythematosus, crow's disease Diseases such as nephritis, pancreatitis, chronic pancreatitis, recurrent nephrolithiasis, chronic prostatitis, vulvovaginal pain syndrome, ankylosing spondylitis, polymyalgia, alcoholic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), HIV-related distal sensory polyneuropathy, Guillain-Barré syndrome, compressive neuropathy (e.g., carpal tunnel syndrome), painful polyneuropathy (idiopathic or nutritional, e.g., vitamin B12 deficiency), post-stroke central pain, multiple sclerosis-related pain, spinal cord injury pain, and spinal cord pain. A composition according to any one of the preceding items, selected from the group consisting of syringomyelia, Parkinson's disease-related pain, thalamic pain syndrome (Dejurine-Lucy syndrome), transverse myelitis, post-ischemic myelopathy, compressive myelopathy due to spinal stenosis, radiotherapy-induced peripheral neuropathy, paraneoplastic sensory neuropathy, tumor-infiltrating neuropathy, post-thoracotomy pain syndrome, leptomeningeal carcinomatosis, paraneoplastic peripheral neuropathy, post-radiation myelopathy, and combinations thereof. (Item 23C) The composition according to any one of the preceding items, wherein the composition is administered by topical, oral, injection, or electrophoretic application. (Item 24C) A composition according to any one of the preceding items, wherein an additional therapeutic agent, a secondary therapy, or a combination thereof is further administered to the subject in combination with the composition. (Item 25C) A composition according to any one of the preceding items, wherein radiotherapy, surgical therapy, immunotherapy, gene therapy, chemotherapeutic agents, nonsteroidal anti-inflammatory agents, and combinations thereof are further administered to the subject in combination with the composition. (Item 26C) The pharmaceutical composition according to any one of the preceding items, wherein the disease is selected from the group consisting of postherpetic neuralgia, diabetic neuropathy, diabetic foot pain due to neuropathy, metatarsalgia, gout, hallux valgus, metatarsalgia, Morton's neuroma, hyperemesis gravidarum syndrome due to cannabis or cannabinoids, postmastectomy pain syndrome, oral neuropathy pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders, synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain due to hip and vertebral disorders, hernia, fibromyalgia, cluster headache, skin diseases, contact dermatitis, Stevens-Johnson syndrome, pain and itching from other inflammatory foci due to skin diseases, skin conditions, erythema, endometriosis, migraine, sciatica, frozen shoulder, vascular occlusive pain due to sickle cell anemia, interstitial cystitis, and combinations thereof. (Item 27C) The aforementioned diseases include postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, phantom limb pain, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, tension headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, joint pain of the neck, hand or fingers, stenotic synovitis, dystrophy of the knee, hip, ankle or wrist, carpal tunnel syndrome, nasal lesions, oral mucositis, skin allergies, hyperdetrusor reflex, and pain caused by anticancer chemotherapy. Pain, isolated pain / hematuria syndrome, cervical pain, pain due to multiple sclerosis, amputee pain, reflex sympathetic dystrophy, complex regional pain syndrome (CRPS) type I (formerly known as reflex sympathetic dystrophy), complex regional pain syndrome (type II; burning pain), allodynia, idiopathic pain, pain due to skin tumors, pain due to spinal cord injury, pain due to foot injury, pain due to fracture, pain due to dislocation, myofascial pain syndrome, systemic lupus erythematosus, Crohn's disease Diseases, pancreatitis, chronic pancreatitis, recurrent nephrolithiasis, chronic prostatitis, vulvovaginal pain syndrome, ankylosing spondylitis, polymyalgia, alcoholic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), HIV-related distal sensory polyneuropathy, Guillain-Barré syndrome, compressive neuropathy (e.g., carpal tunnel syndrome), painful polyneuropathy (idiopathic or nutritional, e.g., vitamin B12 deficiency), post-stroke central pain, multiple sclerosis-related pain, spinal cord injury pain, spinal cord surgery A pharmaceutical composition according to any one of the preceding items, selected from the group consisting of sinusitis, Parkinson's disease-related pain, thalamic pain syndrome (Dejurine-Lucy syndrome), transverse myelitis, post-ischemic myelopathy, compressive myelopathy due to spinal stenosis, radiotherapy-induced peripheral neuropathy, paraneoplastic sensory neuropathy, tumor-infiltrating neuropathy, post-thoracotomy pain syndrome, leptomeningeal carcinomatosis, paraneoplastic peripheral neuropathy, post-radiation myelopathy, and combinations thereof. (Item 28C) The pharmaceutical composition according to any one of the preceding items, wherein the composition is administered by topical, oral, injection, or electrophoretic application route. (Item 29C) A pharmaceutical composition according to any one of the preceding items, wherein an additional therapeutic agent, a secondary therapy, or a combination thereof is further administered to the subject in combination with the composition. (Item 30C) A pharmaceutical composition according to any one of the preceding items, wherein radiotherapy, surgical therapy, immunotherapy, gene therapy, chemotherapeutic agents, nonsteroidal anti-inflammatory agents, and combinations thereof are further administered to the subject in combination with the composition. Summary of Disclosure Disclosed herein are compounds of formula (I) in solid form: [ka] The solid form comprises the solvate, hydrate, or isotope thereof, and is characterized by an X-ray powder diffraction pattern having at least one peak position selected from 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°). Related pharmaceutical compositions and therapeutic methods are also disclosed herein. [Brief explanation of the drawing]

[0015] [Figure 1] This is an HPLC chromatogram of a sample of natural capsaicin. [Figure 2] This is the HPLC chromatogram of a saturated solution (~0.28 mg / mL) of capsaicin palmitate (form P) prepared in Example 1. [Figure 3] This is the NMR spectrum of a sample of natural capsaicin in deuterated chloroform. [Figure 4] This is the NMR spectrum of capsaicin palmitate (morphology P) prepared in Example 1. [Figure 5] This is the XRD diffraction pattern of capsaicin palmitate (morphology P) prepared in Example 1. [Figure 6] This is the XRD diffraction pattern of capsaicin palmitate (morphology T) prepared in Example 2. [Figure 7] We compare the normalized (crystalline phase) signals of morphologies P and T. [Figure 8] The X-ray diffraction patterns of crystal A and crystal B are compared. [Figure 9]The XRD patterns of the crystalline and amorphous phases of morphology P are shown. [Figure 10] The XRD patterns of the crystalline and amorphous phases of morphology T are shown. [Figure 11] This shows the differential scanning calorimetry thermogram trace of morphology P. [Figure 12] This shows the differential scanning calorimetry thermogram trace of morphology T. [Figure 13] This shows the variable temperature powder XRD of morphology P, which leads to the formation of morphology C. [Figure 14] This shows variable temperature powder XRD of morphology T, which leads to the formation of morphology C. [Modes for carrying out the invention]

[0016] This disclosure relates to pharmaceutical compositions and formulations thereof, comprising a solid form of capsaicin palmitate (CP) useful for the treatment of pain. As illustrated in Examples 1 to 6 below, the inventors have discovered a novel solid form of CP (referred to herein as “Form C” or “CP Form C”), distinct from other forms of CP described below.

[0017] Terms and Definitions Before describing this disclosure in more detail, it may be helpful to provide definitions of certain terms used herein. Further definitions are provided throughout this disclosure.

[0018] Where used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the invention (particularly in the context of the claims) should be construed to encompass both singular and plural forms unless otherwise indicated herein or unless the context clearly contradicts this. Any and all examples or exemplary language provided herein (e.g., “etc.”) are intended solely to better illustrate the invention and do not impose any limitation on the scope of the invention as otherwise claimed. The use of alternative terms (e.g., “or”) should be understood to mean one of the options, both, or any combination thereof.

[0019] In this specification, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the enumerated range, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated. Similarly, any range of numbers described herein with respect to any physical characteristic should be understood to include any integer within the described range, unless otherwise indicated. Where a particular quantity or value is used, it should be understood to include a slight deviation from that quantity or value, which a person skilled in the art would understand to be equivalent to or substantially the same as that quantity or value. In some embodiments, a particular quantity or value includes ±10% of the quantity or value. In some embodiments, a particular quantity or value includes ±5% of the quantity or value.

[0020] As used herein, ranges and quantities may be expressed as "approximately" a specific value or range. "Approximately" also includes exact quantities. Therefore, for example, a pH value of "approximately 7" means a pH of approximately 7, and also means a pH of 7. In some embodiments, "approximately" means within 5% of a value. Therefore, a pH of "approximately 7" means a pH in the range of 6.65 to 7.35. In some embodiments, "approximately" means within 4% of a value. In some embodiments, "approximately" means within 3% of a value. In some embodiments, "approximately" means within 2% of a value. In some embodiments, "approximately" means within 1% of a value. Generally, the term "approximately" includes quantities that would be expected to be within experimental error.

[0021] As used herein, the phrase “same or substantially the same” has the same meaning as the term “about” as defined above.

[0022] As used herein, terms such as “administer,” “give delivery,” and “dosage” refer to methods that may be used to enable the delivery of a compound or composition to a desired site of action. Administering a compound or composition described herein to a subject may include administering the compound or composition to a subject topically, orally, parenterally, percutaneously, transmucosally, subcutaneously, or intradermally. Administration techniques that may be used in conjunction with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed., Pergamon, and Remington's, Pharmaceutical Sciences (current ed.), Mack Publishing Co., Easton, PA.

[0023] As used herein, the term “concurrently administered” refers to the presence of two active agents administered to a subject. Concurrently administered active agents may be delivered simultaneously or sequentially.

[0024] As used herein, the terms “to treat,” “to treat,” or “treatment” any disease, condition, or disorder mean the management and care of a patient for the purpose of combating a disease, condition, or disorder, and include the administration of the compounds of the present invention to obtain a desired pharmacological and / or physiological effect. The effect may be therapeutic and this includes partially or substantially achieving one or more of the following results: partially or completely reducing the degree of the disease, condition, or disorder; improving or enhancing a clinical symptom, complication, or indicator associated with the disease, condition, or disorder; or delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or disorder; or eliminating the disease, condition, or disorder. In some embodiments, the effect may be the prevention of the onset of a symptom or complication of the disease, condition, or disorder.

[0025] The terms “combination therapy,” “in combination,” or “pharmaceutical combination” refer to the administration of two or more therapeutic agents for treating a therapeutic condition or disorder described herein. Such administrations include the simultaneous administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single application having fixed ratios of active ingredients. Alternatively, such administrations include the simultaneous administration of each active ingredient in multiple or separate applications. Furthermore, such administrations also include the use of each type of therapeutic agent administered prior to, simultaneously with, or sequentially to each other, without specific time constraints. In each case, the therapeutic regimen provides a beneficial effect of the combination of drugs in treating a condition or disorder described herein.

[0026] The term "effective dose" means the amount administered to a subject that, when administered, produces a beneficial or desired outcome, including clinical results, for example, inhibiting, suppressing, or reducing the symptoms of the condition being treated in the subject compared to a control. For example, the therapeutic effective dose of a single drug for moderate to severe pain may be given across a wide range of unit dosage forms. For example, oxycodone may be prescribed in doses ranging from 5 to 15 mg to 160 mg in continuous release every 4 to 6 hours, depending on the patient and as needed. Tramadol may be prescribed in doses of 50 mg to 100 mg every 4 to 6 hours, up to a maximum of 400 mg per day. Capsaicin may be available as a 0.025% to 0.25% carrier cream and as an 8% over-the-counter (OTC) formulation in a prescription patch.

[0027] The appropriate dosage is known for approved therapeutic agents and depends on the condition of the subject, the type of condition being treated, and the amount of the compound of the present invention used, as reported in the literature, for example, Physician's Desk Reference (71 st It can be adjusted by those skilled in the art according to the dosage recommended in (ed., 2017).

[0028] As used herein, an object "needs" treatment if such object (preferably a human) derives a biological, pharmaceutically or quality-of-life benefit from such treatment.

[0029] As used herein, “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. The term includes mammals such as humans. Typically, an animal is a mammal. A subject also refers to, for example, primates (e.g., humans, males, or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. Preferably, in certain embodiments, the subject is a human.

[0030] Unless otherwise specified, the term “compounds of the disclosure” refers to the compounds of formula (I), as well as isotopically labeled compounds (including deuterium substitutions), and essentially formed moieties (e.g., polymorphs, solvates, and / or hydrates).

[0031] Furthermore, the compounds of the present invention may be obtained in the form of their hydrates or may include other solvents used in their preparation. The compounds of the present invention may, essentially or intentionally, form solvates with pharmaceutically acceptable solvents (including water), and therefore this disclosure is intended to encompass both solvate and non-solvate forms. The term "solvate" refers to a molecular complex of the compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and known to be harmless to the recipient, such as water and ethanol. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0032] The compounds of this disclosure, including their salts, hydrates, and solvates, may form polymorphs either inherently or by design.

[0033] As used herein, “amorphous” refers to the non-crystalline state of a compound, whether solid or solubilizable. For example, “amorphous” refers to a compound that does not have a regular repeating arrangement of molecules or an outer plane.

[0034] Solid form of capsaicin palmitate This disclosure discloses the solid form of capsaicin palmitate.

[0035] One embodiment is a solid form (referred to herein as "Form C" or "CP Form C") of a compound of formula (I):

[0036] [ka] The solid form is characterized by an X-ray diffraction pattern described in the following experimental section, which includes, or comprises the solvate, hydrate, or isotope thereof, and includes at least one peak position selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree of 2θ (±0.2°).

[0037] In another embodiment, the X-ray diffraction pattern of morphology C includes at least two peak positions at a degree 2θ (±0.2°) selected from the group consisting of 5.48, 13.74, 19.22, and 20.06. In another embodiment, the X-ray diffraction pattern of morphology C includes at least three peak positions at a degree 2θ (±0.2°) selected from the group consisting of 5.48, 13.74, 19.22, and 20.06.

[0038] In another embodiment, the X-ray diffraction pattern of form C includes peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree 2θ (±0.2°).

[0039] In another embodiment, the X-ray diffraction pattern of morphology C includes peak positions at 5.48, 13.74, 19.22, and 20.06 at 2θ (±0.2°), and at least one peak position selected from the group consisting of 8.24, 14.65, 15.80, and 18.30. In another embodiment, the X-ray diffraction pattern of morphology C includes peak positions at 5.48, 13.74, 19.22, and 20.06 at 2θ (±0.2°), and at least two peak positions selected from the group consisting of 8.24, 14.65, 15.80, and 18.30.

[0040] In another embodiment, the X-ray diffraction pattern of form C includes peak positions selected from the group consisting of 5.48, 8.24, 13.74, 14.65, 18.30, 19.22, and 20.06 at degrees 2θ (±0.2°).

[0041] In some embodiments, form C is a compound of formula (II):

[0042] [ka] It further comprises the solvate, hydrate, or isotope thereof.

[0043] Pharmaceutical composition This disclosure also includes pharmaceutical compositions comprising CP form C as described herein.

[0044] One embodiment relates to a pharmaceutical composition comprising CP form C (as described in any of the embodiments disclosed herein) and at least one selected from the group consisting of antioxidants, emollients, emulsifiers, humectants, preservatives, and surfactants.

[0045] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein) and at least one selected from the group consisting of antioxidants, emollients, emulsifiers, moisturizers, humectants, preservatives, and surfactants.

[0046] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein) and at least one antioxidant. Non-limiting examples of antioxidants that may be contained in the compositions of this disclosure include, for example, acetylcysteine, ascorbic acid, ascorbic acid polypeptide, ascorbyl dipalmitate, ascorbyl methylsilanol pectinate, ascorbyl palmitate, ascorbyl stearate, BHA, BHT, t-butylhydroquinone, cysteine, cysteine ​​HCl, diamylhydroquinoline, di-t-butylhydroquinone, dicetylthiodipropionate, dioleyltocopherylmethylsilanol, disodium ascorbyl sulfate, distearylthiodipropionate, ditridecylthiodipropionate, dodecyl gallate, erythorbic acid, ascorbic acid esters, ethyl ferlate, ferulic acid, gallic acid esters, hydroquinone, isooctylthioglycolate, kojic acid, magnesium ascorbate, magnesium ascorbyl phosphate, methylsilanol ascorbate, and natural plant antioxidants. Oxidizing agents include, for example, green tea or grape seed extract, nordihydroguaiaretic acid, octyl gallate, phenylthioglycolic acid, potassium ascorbyl tocopheryl phosphate, potassium sulfite, propyl gallate, quinones, rosmarinic acid, sodium ascorbate, sodium bisulfite, sodium erythorbate, sodium metabisulfite, sodium sulfite, superoxide dismutase, sodium thioglycolate, sorbityl furfural, thiodiglycol, thiodiglycolamide, thiodiglycolic acid, thioglycolic acid, thiolactic acid, thiosalicylic acid, tocophereth-5, tocophereth-10, tocophereth-12, tocophereth-18, tocophereth-50, tocopherol, tocophersolan, tocopheryl acetate, tocopheryl linoleate, tocopheryl nicotinate, tocopheryl succinate, tris(nonylphenyl) phosphite, and combinations thereof.

[0047] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein) and at least one emollient. Non-limiting examples of emollients that may be contained in the compositions of this disclosure include, for example, aloe vera activate, aloe extract, Cetiol® MM, Cetiol® OE, cetyl alcohol, Hetester SSS, Jeechem® MM, Lexol® IPL, octyl palmitate, octyl palmitate, neopentyl glycol heptanoate, Performalene 400, neopentyl glycol heptanoate, neopentyl glycol diheptanoate, octyldodecyl neopentanoate, Trivent NP-13, CJ2, and combinations thereof.

[0048] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein) and at least one emulsifier.Non-limiting examples of emulsifiers that may be contained in the compositions of this disclosure include, for example, acrylate / C10-30 alkyl acrylate crosspolymer, alkyl-modified dimethicone copolyol, alkylphenol-hydroxypolyoxyethylene, benzyl alcohol, benzyl benzoate, beeswax / borax, benzalkonium chloride, 1,3-butylene glycol, carbomer, castor oil, cetyl alcohol, ceteareth-20, cholesterol, cholesterol esters, corn germ oil, cottonseed oil, distearyldimethylammonium chloride, dimethylformamide, dicapryl / dicapric acid, disteareth-75 IPDI, ethoxylated difatty acid ester, ethyl alcohol, ethyl carbonate, ethyl acetate, sorbitan fatty acid ester, glycerol, glycerol distearate, glyceryl monostearate, peanut oil, ionic polysorbate surfactant, isopropyl alcohol, nonylphenyl polyethylene glycol ether, nonoxynol-9, octoxynol-40, olive oil, PEG (polyethylene glycol)-100 stearate, PEG-150 distearate, PEG-150 pentaerythrityl tetrastearate, polysorbate 20, phosphatidylcholine, polysorbate, poloxamer 188, poloxamer 407, polyacrylamide, polyquaternium-37, polyethylene Examples include polyethylene glycol 400, polyethylene glycol 8000, poly(oxy-1,2-ethanediyl), polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 15 hydroxystearate, polyoxyl 40 stearate, polysorbate 20, polysorbate 80, propylene glycol, polyglyceryl esters, PPG-1 trideceth-6, polyethylene glycol, sesame oil, sodium lauryl sulfate, sodium docusate, sodium dodecyl sulfate, sodium lauryl stearate, sodium cetearyl sulfonate, steareth 2, steareth 20, steapyrium chloride, taurocholic acid, tetrahydrofurfuryl alcohol, tyroxapol, and combinations thereof.

[0049] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein) and at least one humectant. Non-limiting examples of humectants that may be contained in the compositions of this disclosure include, for example, acetylated lanolin, acetylated lanolin alcohol, acrylate copolymer, alanine, algal extract, Aloe barbadensis, Aloe barbadensis extract, Aloe barbadensis gel, Aracea officinalis extract, aluminum starch octenylsuccinate, aluminum stearate, apricot kernel oil, arginine, arginine aspartate, Arnica montana extract, ascorbic acid, palmitate Ascorbyl tinate, aspartic acid, avocado (Persea grattissima) oil, barium sulfate, variol sphingolipids, butyl alcohol, beeswax, behenyl alcohol, beta-sitosterol, BHT, birch (Betula alba) bark extract, borage (Borago ozinalis) extract, 2-bromo-2-nitropropane-1,3-diol, butcher's broom (Lacus acreatus) extract, butylene glycol, butyrospermum perkyi, calendula extract, calendula oil, candelilla ( Euphorbia cerifera wax, canola oil, caprylic / caprin triglyceride, cardamom (Eletaria cardamomum) oil, carnauba (Copernicia cerifera) wax, carrageenan (Chondras crispus), carrot (Daucus carotaria sativa) oil, castor oil, ceramide, ceresin, ceteareth-5, ceteareth-12, ceteareth-20, cetearyl octanoate, ceteth-20, ceteth-24, cetyl acetate, cetyl octanoate, cetyl phosphate Lumitate, chamomile (Anthemis nobilis) oil, cholesterol, cholesterol ester, cholesteryl hydroxystearate, citric acid, clary (Salvia sclarea) oil, cocoa (Theobroma cacao) butter, coco-caprylate / caprate, coconut (Cocos nucifera) oil, collagen, collagen amino acids, corn (Zea myrrh) oil, fatty acids, decyl oleate, dextrin, diazolidinyl urea, dimethicone copolyol, dimethiconol, dioctyl adipate,Dioctyl succinate, dipentaerythritol hexacaprolate / hexaplate, DMD M hydantoin, DNA, erythritol, ethoxydiglycol, ethyl linoleate, eucalyptus globulus oil, evening primrose (Oenothera biennis) oil, fatty acids, tolktose, gelatin, geranium maculum oil, glucosamine, glucose glutamate, glutamic acid, glycereth-26, glycerin (e.g., vegetable glycerin), glycerol, glyceryl distearate, glyceryl hydroxystearate, glyceryl laurate, glyceryl linoleate, glyceryl myristate, 40 glyceryl oleate Glyceryl stearate, glyceryl stearate SE, glycine, glycol stearate, glycol stearate SE, glycosaminoglycan (Vitis vinifera) seed oil, hazelnut oil (Golden hazel), hazelnut oil (Corylus awelana), hexylene glycol, honey, hyaluronic acid, hybrid safflower (Carthamus tinctorius), hydrogenated castor oil, hydrogenated coco-glyceride, hydrogenated coconut oil, hydrogenated lanolin, hydrogenated lecithin, hydrogenated palm glyceride, hydrogenated palm kernel Oil, hydrogenated soybean oil, hydrogenated animal fat glycerides, hydrogenated vegetable oil, hydrolyzed collagen, hydrolyzed elastin, hydrolyzed glycosaminoglycans, hydrolyzed keratin, hydrolyzed soy protein, hydroxylated lanolin, hydroxyproline, imidazolidinyl urea, iodopropynyl butylcarbamate, isocetyl stearate, isocetyl stearate, isodecyl oleate, isopropyl isostearate, isopropyl lanolate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, Isostearamide DEA, isostearic acid, isostearyl lactate, isostearyl neopentanoate, jasmine (Jasminum officinale) oil, jojoba (Bucus chinensis) oil, kelp, kukui (Aleurites moluccana) nut oil, lactamide MEA, lanes-16, lanes-10 acetate, lanolin, lanolinic acid, lanolin alcohol, lanolin oil, lanolin wax, lavender (Lavender angustifolia) oil, lecithin, lemon (Citrus medica limon) oil, linoleic acid,Linolenic acid, Macadamia Ternifolia nut oil, Magnesium stearate, Magnesium sulfate, Maltitol, Matricaria chamomile lectin oil, Methyl glucose sesquistearate, Methylsilanol PCA, Microcrystalline wax, Mineral oil, Mink oil, Mortierella oil, Myristyl lactate, Myristyl myristate, Myristyl propionate, Dicaprate / Neopentyl glycol dicaprate, Octyldodecanol, Octyldodecyl myristate, Stear Octyldodecyl loyl stearate, octyl hydroxystearate, octyl palmitate, octyl salicylate, octyl stearate, oleic acid, olive (Olea europaea) oil, orange (Citrus aurantium dalsis) oil, palm (Elias gyanensis) oil, palmitic acid, pantethine, panthenol, panthenyl ethyl ether, paraffin, PCA, peach (Prunus persica) kernel oil, peanut (Arachis hypogaea) oil, PEG-8 Cl2-18 ester, PEG-15 cocamine, PEG-150 distearate, PEG-5 thiolactic acid, thiosalicylic acid, tocophereth-5, tocophereth-10, tocophereth-12, tocophereth-18, tocophereth-50, tocopherol, tocophersolan, tocopheryl acetate, tocopheryl linoleate, tocopheryl nicotinate, tocopheryl succinate, and glyceryl isostearate, PEG-5 glyceryl stearate, PEG-30 tris(nonylphenyl) phosphite, glyceryl stearate, PEG-7 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, P EG-20 Methyl Glucose Sesquistearate, PEG-40 Sorbitan Peroleate, PEG-5 Soybean Sterols, PEG-10 Soybean Sterols, PEG-2 Stearate, PEG-8 Stearate, PEG-20 Stearate, PEG-32 Stearate, PEG-40 Stearate, PEG-50 Stearate, PEG-100 Stearate, PEG-150 Stearate, Pentadecalactone, Peppermint (Mentha piperita) Oil, Petrolatum, Phospholipids, Polyaminosaccharide Condensate, Polyglyceryl Diisostearate, Polyquaternium-24, Polysorbate 20, Polysorbate 40, Polysorbate 60,Polysorbate 80, Polysorbate 85, Potassium Myristate, Potassium Palmitate, Potassium Sorbate, Potassium Stearate, Propylene Glycol, Dicaprylic Acid / Propylene Glycol Dicaprate, Propylene Glycol Dioctanoate, Propylene Glycol Diperargonate, Propylene Glycol Laurate, Propylene Glycol Stearate, Propylene Glycol Stearate SE, PVP, Pyridoxine Dipalmitate, Quaternium-15, Quaternium-18 Hectorite, Quater Nium-22, retinal, retinyl palmitate, rice (Oryza sativa) bran oil, rosemary (Rosmarin odyphysialis) oil, rose oil, safflower (Carthumus tinctorius) oil, sage (Salvia odyfinalis) oil, salicylic acid, sandalwood (Santham album) oil, serine, serum protein, sesame (Sesam indicum) oil, shea butter (Butyrospermum palukii), milk powder, sodium chondroitin sulfate, sodium DNA, sodium hyaluronate, sodium lactate, pal Sodium mitinate, sodium PCA, sodium polyglutamate, sodium stearate, soluble collagen, sorbic acid, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate, sorbitol, soybean (glycyne soybean) oil, sphingolipids, squalane, squalene, stearamide MEA-stearate, stearic acid, stearomethyl methicone, stearomethylsilane, stearyl alcohol, glycyrrhetinic acid Examples include stearyl acid, stearyl heptanoate, stearyl stearate, sunflower (Helianthus annuus) seed oil, sweet pea (Prunus amygdalus dulcis) oil, synthetic beeswax, tocopherol, tocopheryl acetate, tocopheryl linoleate, tribehenin, tridecyl neopentanoate, tridecyl stearate, triethanolamine, tristearin, urea, vegetable oil, water, wax, wheat (Trichicum vulgare) germ oil, ylang-ylang (Cananga odorata) oil, and combinations thereof.

[0050] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein) and at least one preservative. Non-limiting examples of preservatives that may be contained in the compositions of this disclosure include, for example, ascorbyl palmitate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caprylyl glycol, cetrimide, chlorhexidine, chlorphenesin, dehydroacetic acid, DMDM ​​hydantoin, ethylhexylglycerin, Euxyl K500, Euxyl K940, Euxyl PE 9010, Germaben II, Germall Plus, glyceryl caprylate, imidazolidinyl urea, kojic acid, methylchloroisothiazolinone, methylisothiazolinone, methyl-, ethyl-, propyl-, and butyl-parabens, Optiphen DP, Optiphen DLP, Paragon II, Paragon III, Paragon MEPB, Paragon Examples include PPM, pentylene glycol, 2-phenoxyethanol, potassium sorbate, propyl gallate, sodium benzoate, sodium metabisulfite, α-tocopherol, tocopheryl acetate, and combinations thereof.

[0051] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein) and at least one surfactant. Non-limiting examples of surfactants that may be contained in the compositions of this disclosure include, for example, cetearyl alcohol, ceteareth-20, glyceryl stearate, polyoxyethylene (20) sorbitan monooleate (commercial brand names such as "Polysorbate 20", Alkest TW 20, Scattics, or Tween® 20), polyoxyethylene (80) sorbitan monooleate (commercial brand names such as "Polysorbate 80", Alkest TW 80, Scattics, or Tween® 80), PEG-100 stearate, PPG-30 cetyl ether such as Hetoxol C3OP (Global Seven), and Glucam P-20 Distearate. PPG-20 methyl glucose ether distearate, PPG-20 methyl glucose ether acetate, PPG-20 sorbitan tristearate, PPG-20 methyl glucose ether distearate, PPG-20 distearate, PPG-15 stearyl ether, PPG-15 stearyl ether benzoate, PPG-15 isohexadecyl ether, PPG-15 stearate, PPG-15 dicocoate, PPG-12 dilaurate, PPG-11 stearyl ether1 dilaurate, PPG-15 stearate, PPG-15 sorbitan tristearate, PPG-20 methyl glucose ether acetate, PPG-20 sorbitan tristearate, PPG-20 methyl glucose ether distearate, PPG-20 methyl glucose ether distearate, PPG-20 sorbitan tristearate, PPG-20 methyl glucose ether distearate, PPG-20 sorbitan tristearate, PPG-20 methyl glucose ether distearate, PPG-20 sorbitan tristearate, PPG-20 methyl glucose ether distearate, PPG-20 sorbitan tristearate, PPG-20 methyl glucose ether distearate, PPG-20 sorbitan tristearate, PPG-20 methyl glucose ether distearate, PPPG-10 cetyl ether, PPG-10 glyceryl stearate, PPG-10 sorbitan monostearate, PPG-10 hydrogenated castor oil, PPG-10 cetyl phosphate, PPG-10 tallow amine, PPG-10 oleamide, PPG-10 cetyl ether phosphate, PPG-10 dinonyl phenolate, PPG-9 laurate, PPG-8 dioqueate, PPG-8 diethylhexylate, PPG-7 lauryl ether, PPG-5 lanolin wax ether, PPG-5 sucrose cocoate, PPG-5 lanolin wax, PPG-4 jojoba alcohol ether, PPG-4 lauryl ether, Promyristol PM-3 (Croda), PPG-3 myristyl ether propionate, Examples include PPG-3 benzyl ether myristate such as STS (Croda), PPG-3 hydrogenated castor oil such as Hetester HCP (Alzo), PPG-3 hydroxylethyl soy amide, PPG-2 cocamide, PPG-2 lanolin alcohol ether, PPG-1 coconut fatty acid isopropanolamide such as Amizett IPC (Kawaken Fine Chemicals), CETIOL® E (BASF), Jeechem® MM (Jeen), and combinations thereof.

[0052] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein) and at least one selected from the group consisting of vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester), Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil.

[0053] In some embodiments, the pharmaceutical composition comprises CP form C (as described in any of the embodiments disclosed herein), vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester) or Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil.

[0054] In some embodiments, the pharmaceutical composition contains CP form C (as described in any of the embodiments disclosed herein) in an amount ranging from about 0.1% to about 10.0% by weight of the total weight of the pharmaceutical composition. In other embodiments, the amount of form C in the pharmaceutical composition is in the range of about 0.1% to about 0.5% by weight, or about 0.5% to about 1.0% by weight, or about 1.0% to about 1.5% by weight, or about 1.5% to about 2.0% by weight, or about 2.0% to about 2.5% by weight, or about 2.5% to about 3.0% by weight, or about 3.0% to about 3.5% by weight, or about 3.5% to about 4.0% by weight, or about 4.0% to about 4.5% by weight, or about 4.5% to about 5.0% by weight, based on the total weight of the pharmaceutical composition. In other embodiments, the content of form P in the pharmaceutical composition is in the range of about 0.1% to about 0.2% by weight, or about 0.2% to about 0.3% by weight, or about 0.3% to about 0.4% by weight, or about 0.4% to about 0.5% by weight, or about 0.5% to about 0.6% by weight, or about 0.5% to about 0.6% by weight, or about 0.6% to about 0.7% by weight, or about 0.7% to about 0.8% by weight, or about 0.8% to about 0.9% by weight, or about 0.9% to about 1.0% by weight.

[0055] Treatment method This disclosure also includes methods for treating a disease using CP form C as described herein.

[0056] One embodiment relates to a method for treating a disease in a subject requiring its use by administering an effective amount of CP form C described herein. Another embodiment relates to a method for treating a disease in a subject requiring its use by administering an effective amount of the pharmaceutical composition described herein.

[0057] Another embodiment relates to the use of CP form C described herein in the manufacture of a pharmaceutical product for treating a disease in a subject that requires it. The disclosure also provides the use of CP form C for treating a disease in a subject that requires it.

[0058] The treatment methods disclosed herein may be applied to a wide variety of diseases, including the following:

[0059] neuropathic pain syndrome Conditions involving nerve damage or dysfunction that often cause burning, stabbing, or electric shock-like pain. These include postherpetic neuralgia, herpes zoster, diabetic neuropathy, diabetic foot pain due to neuropathy, alcoholic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), HIV-related distal sensory polyneuropathy, oral neuropathic pain, trigeminal neuralgia, Guillain-Barré syndrome, compressive neuropathy (e.g., carpal tunnel syndrome), painful polyneuropathy (idiopathic or nutritional, e.g., vitamin B12 deficiency), post-stroke central pain, multiple sclerosis-related pain, spinal cord injury pain, syringomyelia, Parkinson's disease-related pain, and spinal cord injury. Thalamic pain syndrome (Degeran-Roussie syndrome), transverse myelitis, post-ischemic myelopathy, compressive myelopathy due to spinal stenosis, radiation therapy-induced peripheral neuropathy, paraneoplastic sensory neuropathy, tumor-infiltrating neuropathy, paraneoplastic peripheral neuropathy, allodynia, idiopathic pain, reflex sympathetic dystrophy / complex regional pain syndrome (CRPS) type I (formerly known as reflex sympathetic dystrophy), complex regional pain syndrome (type II; burning pain), phantom limb pain, stump pain, Morton's neuroma, sciatica, neck pain, pain from foot injuries.

[0060] Musculoskeletal and joint disorders Pain originating from bones, joints, muscles, ligaments, or tendons, often resulting from degeneration, trauma, or inflammation. This includes conditions such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, neck, hand, or finger joint pain, hand and knee joint disorders, synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain from hip and vertebral disorders, stenotic synovitis, dystrophy of the knee, hip, ankle, or wrist, frozen shoulder (adhesive capsulitis), fibromyalgia, myofascial pain syndrome, gout, hallux valgus, metatarsalgia, pain from fractures, pain from dislocations, herniated discs, polymyalgia rheumatica, and ankylosing spondylitis.

[0061] Inflammatory and visceral / vascular related conditions Pain-causing systemic or local inflammation, often involving joints, skin, or organs. Systemic lupus erythematosus, Crohn's disease, pancreatitis / chronic pancreatitis, vaso-occlusive pain associated with sickle cell anemia, pruritus, uremic pruritus, skin allergies, contact dermatitis, erythema, Stevens-Johnson syndrome. Pain originating from visceral, bladder, or reproductive systems. Endometriosis, interstitial cystitis, hyperdetrusor reflex, chronic prostatitis, vulvodynia, recurrent nephrolithiasis, roan pain / hematuria syndrome, toothache, oral mucositis, rhinopathy. Pain concentrated in the head, face, jaw, or mouth. Cluster headaches, tension headaches, migraines, temporomandibular joint disorders. Skin-related pain or itching due to inflammation, allergies, or tumors. Pain and itching from skin diseases, other inflammatory foci due to skin diseases, skin symptoms, and skin tumors.

[0062] Cancer and treatment-related pain conditions Pain caused by malignant tumors, surgery, or therapies such as chemotherapy / radiation, post-mastectomy pain syndrome, post-thoracotomy pain syndrome, anti-cancer chemotherapy pain, leptomeningeal carcinomatosis, post-radiation myelopathy, cannabis or cannabinoid hyperemesis gravidarum syndrome.

[0063] In the treatment method and use of the present invention, the disease may be selected from postherpetic neuralgia, diabetic neuropathy, diabetic foot pain due to neuropathy, metatarsalgia or gout, hallux valgus, cannabis or cannabinoid hyperemesis syndrome, postmastectomy pain syndrome, oral neuropathy pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders including synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain due to hip and vertebral disorders, hernia, fibromyalgia, cluster headache, skin diseases such as dermatitis, contact dermatitis, Stevens-Johnson syndrome, or skin conditions such as psoriasis, pain and itching from other inflammatory lesions such as pruritus or certain forms of itching, erythema, stinging, or a combination thereof. For example, in some embodiments, the disease is selected from postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and functional joint pain including cervical, hand, finger, knee, hip, and wrist dystrophy, and carpal tunnel syndrome. Pain conditions include rhinitis, oral mucositis, skin allergies, hyperdetrusor reflex, pain from anticancer chemotherapy, isolated pain / hematuria syndrome, neck pain, pain from multiple sclerosis, stump pain, reflex sympathetic dystrophy or complex regional pain syndrome (Type II; burning), allodynia, or idiopathic pain, pain from skin tumors, and combinations thereof. Other conditions include pain from surgical wounds, or painful conditions from trauma including spinal cord and foot injuries, fractures, and dislocations.

[0064] In some embodiments, the disease is selected from the group consisting of postherpetic neuralgia, diabetic neuropathy, diabetic foot pain due to neuropathy, metatarsalgia, gout, hallux valgus, metatarsalgia, Morton's neuroma, hyperemesis gravidarum syndrome due to cannabis or cannabinoids, postmastectomy pain syndrome, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders, synovitis, meniscal tears, anterior and posterior cruciate ligament injuries or dislocations, tendinitis, pain due to hip and spinal disorders, hernia, fibromyalgia, cluster headache, skin diseases, contact dermatitis, Stevens-Johnson syndrome, pain and itching from other inflammatory foci due to skin diseases, skin conditions, erythema, endometriosis, migraine, sciatica, frozen shoulder, vascular occlusive pain due to sickle cell anemia, interstitial cystitis, and combinations thereof.

[0065] In some embodiments, the disease is postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, tension headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, joint pain of the neck, hand or fingers, stenotic synovitis, dystrophy of the knee, hip, ankle or wrist, carpal tunnel syndrome, nasal lesions, oral mucositis, skin allergies, hyperdetrusor reflex, Pain due to anti-cancer chemotherapy, sporadic pain / hematuria syndrome, cervical pain, pain due to multiple sclerosis, stump pain, reflex sympathetic dystrophy, complex regional pain syndrome (CRPS) type I (formerly known as reflex sympathetic dystrophy), complex regional pain syndrome (type II; burning pain), allodynia, idiopathic pain, pain due to skin tumors, pain due to spinal cord injury, pain due to foot injury, pain due to fracture, pain due to dislocation, myofascial pain syndrome, all Physical lupus erythematosus, Crohn's disease, pancreatitis, chronic pancreatitis, recurrent nephrolithiasis, chronic prostatitis, vulvovaginal pain syndrome, ankylosing spondylitis, polymyalgia, alcoholic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), HIV-related distal sensory polyneuropathy, Guillain-Barré syndrome, compressive neuropathy (e.g., carpal tunnel syndrome), painful polyneuropathy (idiopathic or nutritional, e.g., vitamin B12 deficiency), post-stroke central pain, polyneuropathy The following conditions are selected from the group consisting of: sclerosing-related pain, spinal cord injury pain, syringomyelia, Parkinson's disease-related pain, thalamic pain syndrome (Dejurine-Lucy syndrome), transverse myelitis, post-ischemic myelopathy, compressive myelopathy due to spinal stenosis, radiation therapy-induced peripheral neuropathy, paraneoplastic sensory neuropathy, tumor-infiltrating neuropathy, post-thoracotomy pain syndrome, leptomeningeal carcinomatosis, paraneoplastic peripheral neuropathy, post-radiation myelopathy, and combinations thereof.

[0066] In some embodiments, the administration route of CP form C (or the pharmaceutical composition described herein) is by topical administration comprising a carrier vehicle such as a cream, ointment, gel, or patch, or by electrophoresis or oral administration.

[0067] This disclosure also includes combination therapies. For example, in some embodiments, CP form C (or the pharmaceutical composition described herein) is administered concurrently with additional therapeutic agents, secondary therapies, or combinations thereof. Secondary therapies may include, for example, radiotherapy, surgical therapy, immunotherapy, gene therapy, infrared light, electrical stimulation, or combinations thereof. Additional therapeutic agents may include, for example, chemotherapeutic agents, nonsteroidal anti-inflammatory drugs, steroids, anesthetics, other analgesics, or combinations thereof.

[0068] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will be able to conceive of numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in carrying out the invention. The claims set forth below define the scope of the present invention and are intended to thereby cover methods and structures within the scope of these claims, as well as their equivalents. [Examples]

[0069] Abbreviation Cap: Natural capsaicin; CP: Capsaicin palmitate; CDCL3: Deuterated chloroform; DCM: Dichloromethane; DI: Deionization; DMAP: 4-dimethylaminopyridine; EtOH: Ethanol; FTIR: Fourier transform infrared spectroscopy; HPLC: High-pressure liquid chromatography or high-performance liquid chromatography Chromatography; MeCN: Acetonitrile; NMR: nuclear magnetic resonance spectroscopy; ppm: parts per million; XRD: X-ray diffraction; PXRD: Powder X-ray diffraction; RODI: Reverse osmosis deionization; TEA: Triethylamine; TMS: Tetramethylsilane.

[0070] HPLC conditions High-performance liquid chromatography (HPLC) was used to analyze the content and purity of natural capsaicin and palmitic acid capsaicin prepared as described below. The HPLC conditions are summarized in Table 1 below.

[0071] [Table 1]

[0072] Figure 1 shows the HPLC chromatogram of a 0.17 mg / mL solution of natural capsaicin (with a molar ratio of capsaicin to dihydrocapsaicin of 64:36) obtained using the HPLC conditions in Table 1. As shown in Figure 1, natural capsaicin had a retention time of approximately 4.2 minutes using the HPLC conditions in Table 1.

[0073] Figure 2 shows the HPLC chromatogram of a saturated solution (approximately 0.28 mg / mL) of capsaicin palmitate prepared in Example 1 below (with a molar ratio of capsaicin palmitate to dihydrocapsaicin palmitate of 64:36) obtained using the HPLC conditions in Table 1. As shown in Figure 2, capsaicin palmitate had a retention time of approximately 19.1 minutes under the HPLC conditions in Table 1, while dihydrocapsaicin palmitate had a retention time of approximately 21.8 minutes.

[0074] NMR conditions Nuclear magnetic resonance (NMR) spectroscopy was used to analyze the content and purity of natural capsaicin and palmitic acid capsaicin prepared as described below. The NMR conditions are summarized in Table 2 below.

[0075] [Table 2]

[0076] Figure 3 shows the NMR spectrum of a sample of natural capsaicin (with a molar ratio of capsaicin to dihydrocapsaicin of approximately 64:36) obtained using the NMR conditions in Table 2.

[0077] Figure 4 shows the NMR spectrum of capsaicin palmitate (having a molar ratio of capsaicin palmitate to dihydrocapsaicin palmitate of 64:36) prepared in Example 1 below, which was obtained using the NMR conditions in Table 2.

[0078] XRD conditions Morphology P and morphology T of capsaicin palmitate, prepared as described below, were analyzed using X-ray diffraction. The XRD conditions are summarized in Table 3 below.

[0079] [Table 3]

[0080] XRD analysis was performed by mixing each sample with a minimal amount of Krytox® oil to hold the solid particles together and adhere the sample to a nylon loop used as a sample mount. Equipped with a HyPix6000HE detector, CuKα1 α The sample was placed at the center of the goniometer of a Rigaku Oxford Diffraction Synergy-S diffractometer operating with radiation (λ=1.54178 Å). The beam slit was set to position 19 (14% of the total intensity). Data were collected in transmission mode (i.e., Debye-Scherrer mode) at 100 K with a sample-detector distance of 90 mm. Gandolfi scans were performed at multiple kappa angles in the range of 2θ-3° to 45°. The Gandolfi mode eliminates influences from the preferred orientation. Microscopic examination of the sample was also performed to rule out the presence of needles or plates that may easily cause the preferred orientation.

[0081] Example 1: Synthesis of capsaicin palmitate (morphology P)

[0082] [ka]

[0083] 8 kg of methylene chloride (ACS grade) was added to a clean, dry glass reactor (22 L) equipped with a mechanical blade agitator (Teflon®), a bottom stopcock, a condenser cooled with 25°C water, and a solid addition funnel containing 607 g of natural capsaicin (with a capsaicin to dihydrocapsaicin molar ratio of 64:36) (1.27 mol capsaicin + 0.72 mol dihydrocapsaicin) (total 1.9879 mol). The natural capsaicin was then added to the methylene chloride, which was being stirred at room temperature, over a period of approximately 5 minutes to obtain a homogeneous solution of natural capsaicin in methylene chloride.

[0084] Next, the reactor containing a stirred solution of natural capsaicin in methylene chloride is equipped with a dropping funnel for 335 mL (2.37 mol) of triethylamine.

[0085]

number

[0086] Next, the dropping funnel is flushed with 50 mL of methylene chloride, and 664 g (2.39 mol) of palmitoyl chloride is added.

[0087]

number

[0088] First DI water wash. After stirring at ambient temperature for 18 hours, 6 L of deionized (DI) water was added to the reaction mixture over 5 minutes via a dropping funnel. The resulting two-phase mixture was then stirred vigorously (to form a vortex) for 5 minutes. The mixing was then stopped, and the resulting mixture was allowed to stand until phase separation was complete. The bottom (organic) layer was then discharged into an Erlenmeyer flask through the bottom stopcock of the reactor, and the top (aqueous) layer was discharged from the reactor and discarded.

[0089] Second DI water wash. The reactor was then flushed with 100 mL of DI water, and the organic layer (collected from the first DI water wash) was added to the reactor along with 6 L of DI water. The resulting two-phase mixture was mechanically stirred for 5 minutes (to form a vortex). The stirring was then stopped, and the resulting mixture was allowed to stand until phase separation was complete. The bottom (organic) layer was then discharged into an Erlenmeyer flask through the bottom stopcock of the reactor, and the top (aqueous) layer was discharged from the reactor and discarded.

[0090] First HCl wash. The reactor was then flushed with 100 mL of DI water, and the organic layer (collected from the second DI water wash) was added to the reactor along with 6 L of DI water. The resulting two-phase mixture was mechanically stirred (to form a vortex), and 0.6 L of 31.78% hydrochloric acid solution was added via a dropping funnel. The resulting two-phase mixture was then mechanically stirred for 5 minutes. The stirring was then stopped, and the resulting mixture was allowed to stand until phase separation was complete. The bottom (organic) layer was then discharged into an Erlenmeyer flask through the bottom stopcock of the reactor, and the top (aqueous) layer was discharged from the reactor and discarded.

[0091] A second HCl wash was performed. The reactor was then flushed with 100 mL of DI water, and the organic layer (collected from the first HCl wash) was added to the reactor along with 6 L of DI water. The resulting two-phase mixture was mechanically stirred (to form a vortex), and 0.6 L of 31.8% hydrochloric acid solution was added via a dropping funnel. The resulting two-phase mixture was then mechanically stirred for 5 minutes. The stirring was then stopped, and the resulting mixture was allowed to stand until phase separation was complete. The bottom (organic) layer was then discharged into an Erlenmeyer flask through the bottom stopcock of the reactor, and the top (aqueous) layer was discharged from the reactor and discarded.

[0092] First carbonate wash. The reactor was then flushed with 100 mL of DI water, and the organic layer (collected from the second HCl wash) was added to the reactor along with 6 L of DI water. The resulting two-phase mixture was mechanically stirred (to form a vortex), and 6 L of sodium carbonate (Na2CO3) aqueous solution (10% w / w, pH=10.9) was added via a dropping funnel. The resulting two-phase mixture was then mechanically stirred for 5 minutes. The stirring was then stopped, and the resulting mixture was allowed to stand until phase separation was complete. The bottom (organic) layer was then discharged into an Erlenmeyer flask through the bottom stopcock of the reactor, and the top (aqueous) layer was discharged from the reactor and discarded.

[0093] Second carbonate wash. The reactor was then flushed with 100 mL of DI water, and the organic layer (collected from the first carbonate wash) was added to the reactor along with 6 L of DI water. The resulting two-phase mixture was mechanically stirred (to form a vortex), and 6 L of sodium carbonate (Na2CO3) aqueous solution (10% w / w, pH=10.9) was added via a dropping funnel. The resulting two-phase mixture was then mechanically stirred for 5 minutes. The stirring was then stopped, and the resulting mixture was allowed to stand until phase separation was complete. The bottom (organic) layer was then discharged into an Erlenmeyer flask through the bottom stopcock of the reactor, and the top (aqueous) layer was discharged from the reactor and discarded.

[0094] First RODI water wash. Next, the reactor was flushed with 100 mL of DI water, and the organic layer (collected from the second carbonate wash) was added to the reactor along with 6 L of reverse osmosis deionized (RODI) water. The resulting two-phase mixture was mechanically stirred for 5 minutes (to form a vortex). Then, stirring was stopped, and the resulting mixture was allowed to stand until phase separation was complete. The bottom (organic) layer was then discharged into an Erlenmeyer flask through the bottom stopcock of the reactor, and the top (aqueous) layer was discharged from the reactor and discarded.

[0095] Second RODI water wash. Next, the reactor was flushed with 100 mL of RODI water, and the organic layer (collected from the first RODI water wash) was added to the reactor along with 6 L of reverse osmosis deionized (RODI) water. The resulting two-phase mixture was mechanically stirred for 5 minutes (to form a vortex). Then, stirring was stopped, and the resulting mixture was allowed to stand until phase separation was complete. The bottom (organic) layer was then discharged into an Erlenmeyer flask through the bottom stopcock of the reactor, and the top (aqueous) layer was discharged from the reactor and discarded.

[0096] Next, the organic layer (collected from the second RODI water wash) was separated, dried, filtered, and the organic filtrate was evaporated in a pre-weighed round-bottom flask using a rotary evaporator to obtain 53.6 g (yield approximately 4.9%) of purified capsaicin palmitate (CP) product as a yellow solid (hereinafter referred to as "morph P" or "CP morph P").

[0097] CP form P was analyzed by HPLC using the conditions summarized in Table 2. As shown in Figure 2, form P contained a mixture of capsaicin palmitate and dihydrocapsaicin palmitate, with retention times of approximately 19.1 minutes and 21.8 minutes, respectively. Compared with the HPLC chromatogram of natural capsaicin shown in Figure 1, it is clear that capsaicin (as a free acid) is essentially absent in CP form P.

[0098] CP morphology P was also analyzed by NMR using the conditions summarized in Table 2. Figure 4 shows the NMR spectrum of a 19.9 mg sample of morphology P in CDCl3, with TMS as the internal standard. 1 H NMR(500MHz,CDCl3):δ ppm 6.96(d,J=10.0Hz,1H),6.89(d,J=1.0Hz,1H),6.84(d,J=10.0Hz,1H),5.69(br m,1H),5.35(dd,J1=10Hz,J2=2.5Hz,2H),4.41(d,J=7Hz,2H),3.80(s,3H), 2.56(t,J=9.5Hz,2H),2.21(m,3H),1.99(m,1H),1.74(m,2H),1.66(m,2H). Based on the NMR spectrum in Figure 4, CP form P contained approximately 94.5% of the target CP product (with a molar ratio of approximately 64:36 of capsaicin palmitate to dihydrocapsaicin palmitate) and approximately 5.5% palmitic acid, with no detectable amount of capsaicin starting material present.

[0099] Example 2: Synthesis of capsaicin palmitate (morphology T) Known forms of CP were prepared using the methodology based on Examples 1 and 3 described by Singh et al., U.S. Patent No. 7,943,666.

[0100] A mixture of 30.5.0 g (0.099 mol) of natural capsaicin (0.0634 mol of capsaicin + 0.0356 mol of dihydrocapsaicin), 16.7 mL (0.12 mol) of anhydrous triethylamine, and 200 mL of anhydrous dichloromethane was placed in a 1000 mL two-necked round-bottom flask. A condenser with a moisture trap at the top and a dropping funnel were attached to the flask. While maintaining the flask at room temperature, 32.99 g (0.120 mol) of n-palmitoyl chloride was added to the mixture from the addition funnel while stirring. The mixture was refluxed for 3–6 hours, and then stirred at room temperature for 10–15 hours.

[0101] The resulting mixture was transferred to a separatory funnel and washed sequentially with 2 × 500 mL of DI water, 2 × 500 mL of dilute hydrochloric acid, 2 × 500 mL of 10% sodium bicarbonate (NaHCO3), and 3 × 500 mL of brine. The organic layer was then separated, dried overnight over anhydrous magnesium sulfate, filtered, and the organic filtrate was evaporated under vacuum using a rotary evaporator to obtain the capsaicin palmitate product as a yellow solid (hereinafter referred to as "CP form T" or "form T").

[0102] Example 3: XRD comparison of morphological P and T The CP morphology P of Example 1 and the CP morphology T of Example 2 were analyzed by X-ray diffraction (XRD) using the conditions summarized in Table 3.

[0103] Figure 5 shows the XRD diffraction pattern of CP form P (Example 1), and Figure 6 shows the XRD diffraction pattern of comparative CP form T (Comparative Example 2).

[0104] In Figures 5 and 6, the "total" signal (solid line) indicates the presence of a crystalline phase (characterized by distinct peaks) and an amorphous phase (characterized by one or more broad "halos"). The baseline signal (dotted line) is generated from the total signal using the Python algorithm "pybaselines" with a 20th-order polynomial fitting, and corresponds to the signals from the amorphous phase and the background. The baseline signal (dotted line) is then subtracted from the total signal (solid line) to obtain the normalized signal (shaded line) corresponding to the crystalline phase. Finally, the normalized signal (shaded line) was numerically analyzed.

[0105] Figure 7 compares the normalized (crystalline phase) signals for morphologies P and T. Many overlapping peaks exist at the same (or nearly the same) 2θ positions; however, the relative intensities of these overlapping peaks differ between morphologies P and T. This suggests that the crystalline phases of morphologies P and T are composed of two or more different solid morphologies in varying proportions. The 2θ positions and relative intensities of the peaks for morphologies P and T are shown in Tables 4 and 5.

[0106] [Table 4]

[0107] [Table 5]

[0108] As shown in Table 4, the maximum peak of morphology P (I / I) o =1) is,

[0109]

number

[0110]

number

[0111]

number

[0112]

number

[0113]

number

[0114]

Number

[0115]

Number

[0116]

Number

[0117]

Number

[0118]

Number

[0119]

Number

[0120]

Number

[0121]

number

[0122] Equations (1) and (2) have two unknowns, namely, S A , and S B This represents two equations having the following properties. Using algebraic operations, the diffraction patterns of crystal A and crystal B can be expressed as follows:

[0123]

number

[0124] Figure 8 shows the diffraction patterns of crystals A and B, calculated using equations (3) and (4). The peaks differ between the two crystals, indicating that the spectrograms of morphology P and morphology T are precisely separated into contributions from crystals A and B, and that no other crystals are present in either morphology P or morphology T. The 2θ positions and relative intensities of the peaks for crystals A and B are shown in Tables 7 and 8 below, respectively, along with the corresponding d-intervals for each peak, calculated by Bragg's relation for λ = 1.54178 Å. In Tables 4 and 5, each peak measured for morphology P and morphology T is assigned to either crystal A or crystal B, respectively, based on the corresponding peak found in Tables 6 and 7.

[0125] [Table 6]

[0126] [Table 7]

[0127] The spectrograms shown in Figures 6 and 7 also show contributions from the crystalline phase, amorphous phase, and background signal not attributable to the sample being measured. To determine the crystallinity of morphologies P and T, it is necessary to separate the amorphous phase signal from the background signal. A diffraction pattern for the sample holder only is obtained, which represents the background signal present in Figures 5 and 6.

[0128] Figure 9 includes the diffraction pattern from the sample holder (partially dashed line) plotted with the total diffraction pattern for morphology P (solid line) along with the calculated baseline (dotted line) representing amorphous and background components, and Figure 10 includes the diffraction pattern from the sample holder (partially dashed line) plotted with the total diffraction pattern for morphology T (solid line) along with the calculated baseline (dotted line) representing amorphous and background components. In these figures, the diffraction pattern from the sample holder is scaled so that the flat portion of the calculated baseline at 2q=7° matches the flat portion of the spectrogram of the sample holder at the same position. Then the crystalline fraction (X c This can be calculated using the following equation (5), and the amorphous fraction (X a ) is considered to be the remainder. X c =A c / ( A c +A a ), (5) In the formula, as shown in Figures 9 and 10, the crystal area A c This is the area between the total spectrogram (solid line) and the amorphous + background (baseline, dotted line) diffraction pattern, A a This represents the area between the amorphous + background (baseline, dotted line) diffraction pattern and the diffraction pattern of the sample holder (partially dashed line). X for morphology P c It is calculated that 20% is crystalline (i.e., morphology P is 20% crystalline and 80% amorphous), and X for morphology T c This is 35% (i.e., morphology T is 35% crystalline and 65% amorphous).

[0129] Unlike the crystalline phase, which produces diffraction patterns with narrow peaks, the diffraction pattern of the amorphous phase consists of a broad "halo." For morphology P, the halo with the maximum amplitude is:

[0130]

number

[0131]

number

[0132] The X-ray diffraction data for morphology P and morphology T show differences that can be used to distinguish between these solid morphologies. These differences are summarized in Table 8 below.

[0133] [Table 8]

[0134] Example 4: DSC comparison of morphology P and T Morphology P and T were analyzed using differential scanning calorimetry (DSC). DSC measurements were performed using a TA Instruments Q2000 with indium temperature calibration. For each measurement, approximately 3–5 mg of sample was weighed into a lidded Tzero aluminum pan, crimped, and loaded into the DSC instrument. An empty pan of the same configuration was loaded into the reference position. The sample was heated from -30°C to 75°C, equilibrated at 75°C, cooled to -30°C at 10°C / min, equilibrated at -30°C, and then heated to 100°C at 10°C / min. The DSC cell was maintained under nitrogen purging of approximately 50 mL / min during each analysis. Data acquisition was performed using Thermal Advantage 5.5.3 software, and data analysis was performed using Trios v5.0.0.44608. Figures 11 and 12 show DSC thermograms of morphology P and T, respectively.

[0135] DSC traces of morphologies P and T were collected by starting at room temperature, then cooling to -80°C, and subsequently heating above the melting point (300°C). Morphologies P and T ultimately melt at similar temperatures, approximately 62°C. Both samples exhibited multiple thermal events between approximately 30 and 70°C. Morphology P shows three complex endothermic events peaking at 35.8, 48.4, and 60.6°C, creating a further shoulder between the first and second events. The second and third events appear to resolve completely once the signal reaches the baseline, although the steep slope near the baseline is atypical. Morphology T shows only two endothermic events separated by an exothermic range. The series of endothermic-exothermic-endothermic events indicates melting-recrystallization of the low-melting-point crystalline phase, followed by melting of the high-melting-point crystalline phase. The low-temperature shoulder of the first event appears to coincide with the shoulder of the second event for morphology P.

[0136] Morphology P exhibits three endothermic phases, while morphology T exhibits only two. There may be two phases involved in endothermic activity, which could also indicate different orientations of molecular interactions. Between 30°C and 47°C, with a melting point of 62–64°C, there were potentially multiple phase transition events.

[0137] Example 5: Variable temperature PXRD analysis (Preparation of morphology C) Based on the DSC comparison in Example 4, it was theorized that changes in the crystal structure of morphologies P and T can occur at high temperatures. To study the temperature-dependent changes in crystal structure, variable-temperature powder X-ray diffraction (VT-PXRD) was performed on morphologies P and T within the same temperature range as the DSC thermal events. The PRXD conditions are summarized in Table 9 below.

[0138] [Table 9]

[0139] Temperature changes were performed using an Anton Paar CHC+ variable temperature / humidity chamber and an Anton Paar CCU 100 controller. The temperature outside the sample chamber was maintained at 20°C using a Julabo Corio CD-201F cooling circulator. The cooling mode of the sample holder was passive.

[0140] The temperature cycling of the two samples was started at room temperature (RT). Data acquisition began when the target temperature was reached, and VT-PXRD patterns were continuously collected for a total of approximately 30 minutes at each temperature. Data acquisition during cooling began immediately after heating was stopped. The collected patterns were separated with a 15-minute retention period, totaling slightly over 3 hours, and then scanned while cooled to room temperature.

[0141] When the sample was heated to 35°C and held, there was little discernible change in the VT-PXRD pattern compared to the starting material. When heated to 45°C and 47°C, the peaks observed at room temperature began to decrease. At 52°C, new peaks appeared, indicating a new and different crystalline phase. Between 62 and 64°C, most of these new peaks disappeared, the sample melted, and appeared translucent. The moment heating was stopped, the sample became opaque, and the PXRD pattern peaks present at 52°C reappeared, indicating that the sample had recrystallized.

[0142] After cooling to room temperature (RT), as indicated by the peak shifts from starting materials P and T, recrystallization of forms P and T was found to result in phase transitions to new crystal form C, respectively. As shown in FIGS. 13 and 14, the room temperature peaks after the heating / cooling cycle were identical for form P (FIG. 13) and form T (FIG. 14). This data indicates that both crystals A and B underwent a conversion to a stable and unique polymorphic form (which is mainly composed of new crystal C), herein referred to as "form C" or "CP form C".

[0143] As shown in FIGS. 13 and 14, the peak of form C was present at 52 °C, and before reaching 52 °C, the peaks of the initial forms P and T disappeared. At room temperature, the peak of form C for forms P and T was not present (except for a very weak peak at 5.48°). The peak of form C disappeared during melting at 62 °C / 64 °C and reappeared after cooling to room temperature. The transitions of forms P and T

[0144] [Number] involved significant peak formation. The characteristic 2θ peaks of form C are shown in Table 10.

[0145] [Table 10]

[0146] Example 6: Preparation of a topical analgesic cream containing CP form C Using CP form C of Example 5, a topical analgesic cream having the composition summarized in Table 10 below was prepared.

[0147] In the main tank, the components of phase A were combined while mechanically stirring at 70-75°C to obtain a homogeneous (liquid) mixture. In another tank, the components of phase B were combined while mechanically stirring at 70-75°C to obtain a homogeneous (liquid) mixture. Both phase A and phase B were brought to 70-75°C, and the phase B mixture was slowly added to the phase A mixture. The resulting mixture was mechanically stirred at 70-75°C to obtain a homogeneous (liquid) mixture. Next, the phase A / B mixture wax was cooled to 40-45°C using mechanical stirring, and the phase A / B mixture was brought below 45°C. Phase C was added using mechanical stirring, and stirring was continued until the resulting phase A / B / C mixture was homogeneous. Then, in another tank, the components of phase D were combined and heated while mechanically stirring at a temperature of 40-45°C until homogeneous (until there were no undissolved solids). Both phases were heated to 40-45°C, and the Phase D mixture was added to the Phase A / B / C mixture. The resulting mixture was mechanically stirred until smooth and uniform to obtain the topical analgesic cream shown in Table 11.

[0148] [Table 11]

[0149] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced herein are included in U.S. Patent Application No. 63 / 504,132, filed on 24 May 2023, which are incorporated herein by reference in their entirety. The aspects of the embodiments can be modified, where necessary, to provide further embodiments using concepts from various patents, specifications, and publications.

[0150] In consideration of the above-mentioned "modes for carrying out the invention," these and other modifications can be made to the embodiments. In general, the terms used in the following claims should not be interpreted as limiting the claims to the specific embodiments disclosed in the specification and claims, but rather as encompassing all possible embodiments and the full scope equivalent to any such claims. Accordingly, the claims are not limited by the disclosure herein.

Claims

1. A solid form of capsaicin palmitate, which is a compound of formula (I): 【Chemistry 12】 Alternatively, a solid form comprising a solvate, hydrate, or isotope thereof, wherein the solid form is characterized by an X-ray diffraction pattern having at least one peak position selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree 2θ (±0.2°).

2. The solid-state according to claim 1, wherein the X-ray diffraction pattern includes at least two peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree 2θ (±0.2°).

3. The solid form according to claim 1, wherein the X-ray diffraction pattern includes at least three peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree 2θ (±0.2°).

4. The solid form according to claim 1, wherein the X-ray diffraction pattern includes peak positions selected from the group consisting of 5.48, 13.74, 19.22, and 20.06 at a degree 2θ (±0.2°).

5. The solid form according to claim 1, wherein the X-ray diffraction pattern includes peak positions of 5.48, 13.74, 19.22, and 20.06 at degrees 2θ (±0.2°), and at least one peak position selected from the group consisting of 8.24, 14.65, 15.80, and 18.

30.

6. The solid form according to claim 1, wherein the X-ray diffraction pattern includes peak positions of 5.48, 13.74, 19.22, and 20.06 at degrees 2θ (±0.2°), and at least two peak positions selected from the group consisting of 8.24, 14.65, 15.80, and 18.

30.

7. The solid form according to claim 1, wherein the X-ray diffraction pattern includes peak positions selected from the group consisting of 5.48, 8.24, 13.74, 14.65, 15.80, 18.30, 19.22, and 20.06 at a degree 2θ (±0.2°).

8. The solid form according to claim 1, further comprising at least one palmitate ester formed from a congener of capsaicin.

9. Compound of formula (II): 【Chemistry 13】 The solid form according to claim 1, further comprising a solvate, hydrate, or isotope thereof.

10. A pharmaceutical composition, The solid form described in claim 1, A pharmaceutical composition comprising at least one selected from the group consisting of antioxidants, emollients, emulsifiers, humectants, preservatives, and surfactants.

11. The pharmaceutical composition according to claim 10, comprising at least one antioxidant.

12. The pharmaceutical composition according to claim 10, comprising at least one emollient agent.

13. The pharmaceutical composition according to claim 10, comprising at least one emulsifier.

14. The pharmaceutical composition according to claim 10, comprising at least one humectant.

15. The pharmaceutical composition according to claim 10, comprising at least one preservative.

16. The pharmaceutical composition according to claim 10, comprising at least one surfactant.

17. The pharmaceutical composition according to claim 10, comprising at least one selected from the group consisting of vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester), Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil.

18. The pharmaceutical composition according to claim 10, comprising vegetable glycerin, sunflower oil, shea butter, Cetiol® MM (tetradecanoic acid, tetradecyl ester) or Jeechem® MM (myristic acid, myristyl ester), cetyl alcohol, ceteareth-20 (polyethylene glycol ether of cetearyl alcohol), glyceryl stearate, stearic acid, Euxyl® PE 9010 (phenoxyethanol / ethylhexylglycerin), Tween® 80 (polysorbate 80, polyoxyethylene sorbitan monooleate), and coconut oil.

19. A composition comprising the solid form described in claim 1 for treating pain from a disease in a person in need thereof.

20. A pharmaceutical composition according to claim 10 for treating pain from a disease in a person in need thereof.

21. The composition according to claim 19, wherein the disease is selected from the group consisting of postherpetic neuralgia, diabetic neuropathy, diabetic foot pain due to neuropathy, metatarsalgia, gout, hallux valgus, metatarsalgia, Morton's neuroma, hyperemesis gravidarum syndrome due to cannabis or cannabinoids, postmastectomy pain syndrome, oral neuropathy pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders, synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain due to hip and vertebral disorders, hernia, fibromyalgia, cluster headache, skin diseases, contact dermatitis, Stevens-Johnson syndrome, pain and itching from other inflammatory foci due to skin diseases, skin conditions, erythema, endometriosis, migraine, sciatica, frozen shoulder, vascular occlusive pain due to sickle cell anemia, interstitial cystitis, and combinations thereof.

22. The aforementioned diseases include postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, phantom limb pain, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, tension headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, joint pain of the neck, hand or fingers, stenotic synovitis, dystrophy of the knee, hip, ankle or wrist, carpal tunnel syndrome, nasal lesions, oral mucositis, skin allergies, hyperdetrusor reflex, and anticancer chemotherapy. Pain due to, isolated pain / hematuria syndrome, cervical pain, pain due to multiple sclerosis, stump pain, reflex sympathetic dystrophy, complex regional pain syndrome (CRPS) type I (formerly known as reflex sympathetic dystrophy), complex regional pain syndrome (type II; burning pain), allodynia, idiopathic pain, pain due to skin tumors, pain due to spinal cord injury, pain due to foot injury, pain due to fracture, pain due to dislocation, myofascial pain syndrome, systemic lupus erythematosus Crohn's disease, pancreatitis, chronic pancreatitis, recurrent nephrolithiasis, chronic prostatitis, vulvovaginal pain syndrome, ankylosing spondylitis, polymyalgia, alcoholic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), HIV-related distal sensory polyneuropathy, Guillain-Barré syndrome, compressive neuropathy (e.g., carpal tunnel syndrome), painful polyneuropathy (idiopathic or nutritional, e.g., vitamin B12 deficiency), post-stroke central pain, multiple sclerosis-related pain, spinal cord pain The composition according to claim 19, selected from the group consisting of injury pain, syringomyelia, Parkinson's disease-related pain, thalamic pain syndrome (Dejurine-Lucy syndrome), transverse myelitis, post-ischemic myelopathy, compressive myelopathy due to spinal stenosis, radiotherapy-induced peripheral neuropathy, paraneoplastic sensory neuropathy, tumor-infiltrating neuropathy, post-thoracotomy pain syndrome, leptomeningeal carcinomatosis, paraneoplastic peripheral neuropathy, post-radiation myelopathy, and combinations thereof.

23. The composition according to claim 19, wherein the composition is administered by topical, oral, injection, or electrophoretic application route.

24. The composition according to claim 19, wherein an additional therapeutic agent, a secondary therapy, or a combination thereof is further administered to the subject in combination with the composition.

25. The composition according to claim 19, wherein radiotherapy, surgical therapy, immunotherapy, gene therapy, chemotherapeutic agents, nonsteroidal anti-inflammatory agents, and combinations thereof are further administered to the subject in combination with the composition.

26. The pharmaceutical composition according to claim 20, wherein the disease is selected from the group consisting of postherpetic neuralgia, diabetic neuropathy, diabetic foot pain due to neuropathy, metatarsalgia, gout, hallux valgus, metatarsalgia, Morton's neuroma, hyperemesis gravidarum syndrome due to cannabis or cannabinoids, postmastectomy pain syndrome, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, wrist and knee joint disorders, synovitis, meniscal tears, anterior and posterior cruciate ligament tears or dislocations, tendinitis, pain due to hip and vertebral disorders, hernia, fibromyalgia, cluster headache, skin diseases, contact dermatitis, Stevens-Johnson syndrome, pain and itching from other inflammatory foci due to skin diseases, skin conditions, erythema, endometriosis, migraine, sciatica, frozen shoulder, vascular occlusive pain due to sickle cell anemia, interstitial cystitis, and combinations thereof.

27. The aforementioned diseases include postherpetic neuralgia, herpes zoster, postmastectomy pain syndrome, phantom limb pain, oral neuropathic pain, trigeminal neuralgia, temporomandibular joint disorder, pruritus, uremic pruritus, cluster headache, tension headache, toothache, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, joint pain of the neck, hand or fingers, stenotic synovitis, dystrophy of the knee, hip, ankle or wrist, carpal tunnel syndrome, nasal lesions, oral mucositis, skin allergies, hyperdetrusor reflex, and cancer chemotherapy. Sporadic pain, isolated pain / hematuria syndrome, cervical pain, pain due to multiple sclerosis, stump pain, reflex sympathetic dystrophy, complex regional pain syndrome (CRPS) type I (formerly known as reflex sympathetic dystrophy), complex regional pain syndrome (type II; burning pain), allodynia, idiopathic pain, pain due to skin tumors, pain due to spinal cord injury, pain due to foot injury, pain due to fractures, pain due to dislocations, myofascial pain syndrome, systemic lupus erythematosus, Crohn's disease, pancreatitis, chronic pancreatitis, recurrent nephrolithiasis, chronic prostatitis, vulvovaginal pain syndrome, ankylosing spondylitis, polymyalgia, alcoholic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), HIV-related distal sensory polyneuropathy, Guillain-Barré syndrome, compressive neuropathy (e.g., carpal tunnel syndrome), painful polyneuropathy (idiopathic or nutritional, e.g., vitamin B12 deficiency), post-stroke central pain, multiple sclerosis-related pain, spinal cord injury A pharmaceutical composition according to claim 20, selected from the group consisting of pain, syringomyelia, Parkinson's disease-related pain, thalamic pain syndrome (Dejurine-Lucy syndrome), transverse myelitis, post-ischemic myelopathy, compressive myelopathy due to spinal stenosis, radiotherapy-induced peripheral neuropathy, paraneoplastic sensory neuropathy, tumor-infiltrating neuropathy, post-thoracotomy pain syndrome, leptomeningeal carcinomatosis, paraneoplastic peripheral neuropathy, post-radiation myelopathy, and combinations thereof.

28. The pharmaceutical composition according to claim 20, wherein the composition is administered by topical, oral, injection, or electrophoretic application route.

29. The pharmaceutical composition according to claim 20, wherein an additional therapeutic agent, a secondary therapy, or a combination thereof is further administered to the subject in combination with the composition.

30. The pharmaceutical composition according to claim 20, wherein radiotherapy, surgical therapy, immunotherapy, gene therapy, chemotherapeutic agents, nonsteroidal anti-inflammatory agents, and combinations thereof are further administered to the subject in combination with the composition.

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