Repeated topical application of capsaicin patch to treat early non-responders

Abstract

To provide a means for making topical treatment of peripheral neuropathic pain with capsaicin available to patients who do not initially respond to high concentration topical capsaicin dosage units such as high concentration topical patches or creams.SOLUTION: One or more high concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5% by weight relative to the total weight of the dose unit for use in the relief of neuropathic pain in patients who did not perceive a pain relief of at least 30% relative to baseline on the Numeric Rating Scale (NRS) after 8 weeks of administration upon prior topical administration of capsaicin and / or capsaicinoid.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS Priority is claimed of European Patent Application No. 20 163 651.1 filed on March 17, 2020, European Patent Application No. 20 167 982.6 filed on April 3, 2020, and European Patent Application No. 20 173 133.8 filed on May 6, 2020.

[0002] The present invention relates to the repeated treatment of neuropathic conditions, preferably peripheral neuropathic pain, by application of one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably high concentration capsaicin and / or capsaicinoid patches, to patients who have previously failed to respond or responded inadequately to prior application of one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably prior topically administered high concentration capsaicin and / or capsaicinoid patches, or any other high concentration capsaicin and / or capsaicinoid formulations. [Background technology]

[0003] Capsaicin is a highly selective agonist for the transient receptor potential vanilloid 1 receptor (TRPV1). The initial effect of capsaicin is activation of TRPV1-expressing cutaneous nociceptors, resulting in erythema and irritation due to the release of vasoactive neuropeptides. After capsaicin exposure, cutaneous nociceptors become less sensitive to various stimuli. These later effects of capsaicin are often referred to as "desensitization" and are thought to underlie pain relief. Sensation from non-TRPV1-expressing cutaneous nerves is expected to remain unaltered, including the ability to detect mechanical and vibratory stimuli. Capsaicin-induced alterations of cutaneous nociceptors are reversible, and normal function (detection of noxious sensations) has been reported and observed to return within several weeks in healthy volunteers. F. Peppin et al., Ther Adv Neurol Disord (2014) 7(1) 22-32, reviewed the use of capsaicinoids in the treatment of neuropathic pain.

[0004] Low-concentration capsaicin creams, lotions, and patches (0.025% to 0.1% capsaicin by weight) have been available in most countries since the early 1980s for routine topical application. These topical preparations are typically self-administered and often do not require a prescription. Clinical studies have demonstrated that topical dermal applications 3 to 5 times per day over a 2- to 6-week period have modest beneficial effects on various pain syndromes, including postherpetic neuralgia, diabetic neuropathy, and chronic musculoskeletal pain (see V. Fattori et al., Molecules 2016, 21, 844, 1-33).

[0005] Medium-concentration capsaicin patches have been tested in clinical trials. For example, J.-Y. Moon et al., Pain Physician 2017, 20:27-35, reported the efficacy of 0.625% (50 μg / cm) capsaicin in peripheral neuropathic pain. 2 ) and 1.25% (100 μg / cm 2 ) reported on the effectiveness and safety of capsaicin patches.

[0006] High concentration capsaicin topical dosage forms such as liquids, creams or oils are known from, for example, WO2004 / 091521, WO2005 / 117981, WO2013 / 036961, WO2015 / 160941, US 6,248,788, US 7,771,760, US 8,367,733, US 8,802,736.

[0007] W.R. Robbins et al., Anesth Analg 1998 86 579-83, reported on the treatment of intractable pain with topical high-dose capsaicin. Webster et al., Journal of Pain, 3(4)S72 2012 and M. Wallace et al., PainWeek 2014, reported on a clinical trial using a topical liquid formulation of capsaicin in patients with postherpetic neuralgia.

[0008] A high-concentration capsaicin topical cream (8%) has been developed and suggested for the treatment of myofascial pain syndrome. In a placebo-controlled study, patients were asked to indicate their most painful trigger point during a physical examination. This trigger point was demarcated using a 24-mm diameter circular mold equipped with a stylus for application to the skin. 10 g of capsaicin 8% cream was applied to the demarcated skin area for 30 minutes. The authors concluded that topically applied capsaicin 8% demonstrated significant analgesic effects in patients with myofascial pain syndrome. This analgesia persisted for nearly two months after a single application without significant side effects (V. Romero et al., Rev Bras Anestesiol. 2019, 69(5), 432-438).

[0009] High concentration capsaicin patches are known, for example, from US 2001 00002406, US 6,248,788, US 2004 0202707, and US 2014 0335150.

[0010] High-concentration capsaicin patches (179 mg or 8% by weight) are commercially available (Qutenza®) with capsaicin concentrations approximately 100 times higher than conventional creams (see, e.g., US 6,239,180). 2 The skin patch is 2 Each patch contains a total of 179 mg of capsaicin or 640 micrograms of capsaicin. Each patch is 14 cm x 20 cm and consists of an adhesive side containing the active ingredient and an outer backing layer. The adhesive side is covered with a removable, clear, unprinted, diagonally cut release liner. The skin patch is applied to the most painful skin area (use up to four patches).

[0011] High-concentration capsaicin patches are indicated for the treatment of peripheral neuropathic pain in adults, either alone or in combination with other medications, and for the treatment of postherpetic neuralgia in the United States. The efficacy of a single application of high-concentration capsaicin patches has been shown to be maintained for up to 12 weeks in multiple randomized, controlled clinical trials. High-concentration capsaicin patch treatments can be repeated approximately every 3 months.

[0012] The use of 8% capsaicin patches in the management of neuropathic pain has been reviewed by several authors. G. Baranidharan et al., Ther Adv Neurol Disord 2013 6(5)287-297, reviewed high-concentration capsaicin patches and their experience in the management of neuropathic pain. T. Wagner et al., Pain Medicine 2013 14 1202-1211, provided a retrospective analysis of capsaicin 8% patches for neuropathic pain in clinical practice. H.A. Blair, Drugs 2018 78 1489-1500, reviewed capsaicin 8% skin patches in the treatment of peripheral neuropathic pain.

[0013] A. Papagianni et al., PAIN Reports 2018 3 e644 1-9, reported that an 8% capsaicin patch reversibly reduced the amplitude of A-delta fiber evoked potentials. P. Anand et al., Journal of Pain Research 2019 12 2039-2052, reported on pain relief and disease improvement in the rational treatment of chemotherapy-induced peripheral neuropathy with an 8% capsaicin patch.

[0014] The 8% capsaicin patch has been the subject of various clinical trials. For example, M. Miroslav et al., Pain Medicine 2010 11 600-608, reported a randomized, double-blind, controlled study with an open-label extension of NGX-4010, a high-concentration capsaicin patch. L.R. Webster et al., Diab Res Clin Pract 2011 93 187-197, reported the efficacy, safety, and tolerability of the NGX-4010 capsaicin 8% patch in an open-label study in patients with peripheral neuropathic pain. D.B. Clifford et al., J Acquir Immune Defic Syndr 2012 59(2) 126-133, reported a randomized, double-blind, controlled study of NGX-4010, an 8% capsaicin skin patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. S. Brown et al., AIDS Res Ther. 2013 10(1):5, report a pooled analysis of two phase III randomized controlled trials of NGX-4010, an 8% capsaicin patch, for the treatment of painful HIV-associated distal sensory polyneuropathy.

[0015] Several clinical trials have focused on the treatment of postherpetic neuralgia. L.R. Webster et al., BMC Neurology 2010 10 92 1-11, reported on the effect of postherpetic neuralgia duration on efficacy analysis in a multicenter, randomized, controlled study of NGX-4010, an 8% capsaicin patch evaluated for the treatment of postherpetic neuralgia. L.R. Webster et al., The Journal of Pain 2010 11(10) 972-982, reported on a multicenter, randomized, double-blind, dose-ranging study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. G.I. Irving et al., Pain Medicine 2011 12 99-109, reported on a multicenter, randomized, double-blind, controlled trial of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. LR Webster et al., BMC Anesthesiology 2011 11 25 1-8, reported on the tolerability of NGX-410, an 8% capsaicin skin patch, following pretreatment with lidocaine 2.5% / prilocaine 2.5% cream in patients with postherpetic neuralgia. MM Backonja et al., Pain Med. 2010 11(4):600-8, reported on NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled trial with an open-label extension.

[0016] C. Maihofner et al., CMRO 2013 29(6) 673-683, report the first results of a prospective, non-interventional study of the tolerability and analgesic effect of a single application of an 8% capsaicin skin patch over 12 weeks in 1,044 patients with peripheral neuropathic pain (QUEPP study). C. Maihofner et al., Eur J Pain 2014 18 671-679, report the effect of pre-existing pain on the treatment of peripheral neuropathic pain with topical capsaicin in the QUEPP study.

[0017] C. Mankowski et al., BMC neurology 2017 17 80 2-11, reported on the effectiveness of capsaicin 8% patches in the management of peripheral neuropathic pain in European clinical practice (ASCEND study).

[0018] 8% capsaicin patches have been reported to be particularly useful in treating refractory neuropathic pain syndromes. M. Gimenez-Milla et al., BMC Anesthesiology 2014 14 120 1-7, reported on the feasibility evaluation of high-concentration capsaicin patches in a tertiary care hospital pain unit for a population of mixed refractory peripheral neuropathic pain syndromes in non-diabetic patients. P. Bardo-Brouard et al., Curr Med Res Opin 2018 34(5) 887-891, reported on a case series of high-concentration topical capsaicin in the management of refractory neuropathic pain in patients with neurofibromatosis type 1.

[0019] Long-term and repeated treatment with high-concentration capsaicin patches has been investigated in an open-label extension study of a randomized controlled clinical trial and two larger, single-agent clinical trials. DMSimpson et al., J Pain Symptom Manag 2010 39(6)1053-1064, reported on the long-term safety of NGX-4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain. A preliminary investigation of repeated high-concentration capsaicin patches in a 52-week randomized controlled clinical trial in patients with painful diabetic peripheral neuropathy showed that the use of high-concentration capsaicin patches in addition to standard treatment demonstrated superior efficacy compared with standard treatment alone (PACE study, AI Vinik et al., BMC Neurology 2016 16 251 1-14). Similarly, in a 52-week study in patients with non-diabetic peripheral neuropathic pain, a subset of patients (n=100) received four consecutive capsaicin 8% patch treatments, a decrease in average daily pain was observed after each successive capsaicin and / or capsaicinoid treatment, with pain relief sustained between treatments (STRIDE study, R. Galvez et al. Clin J Pain 2017 33(10)921-931).

[0020] A problem with conventional treatment of neuropathic pain with topical application of high-concentration capsaicin patches is the non-response of a significant number of patients. N.P. Katz et al., Clin J Pain 2015 31(10) 859-866, reported on predictors of response in patients with herpes simplex neuralgia and HIV-associated neuropathy after treatment with an 8% capsaicin patch (Qutenza®). Ch. Martini et al., Journal of Pain Research 2012 5 51-59, reported that the treatment of chronic pain is associated with high variability in response to pharmacological interventions. A mathematical pharmacodynamic model was developed to quantify the effect size and onset / offset time of a single application of an 8% capsaicin patch in the treatment of painful diabetic peripheral neuropathy in 91 patients. The model identified four distinct subgroups that responded differently to treatment: 3.3% of patients (subgroup 1) showed worsening pain; 31% (subgroup 2) showed no change; 32% (subgroup 3) showed a rapid decrease in pain that reached a nadir at week 3, followed by a slow return to baseline (16% ± 6% pain decrease at week 12); and 34% (subgroup 4) showed a rapid decrease in pain that persisted (70% ± 5% decrease at week 12). This analysis allowed us to separate the heterogeneous neuropathic pain population into four homogeneous subgroups with distinct behaviors in response to capsaicin treatment.

[0021] Thus, there are a significant number of patients who do not respond adequately to topical treatment with high-concentration capsaicin (e.g., 8% capsaicin patch or cream) and treatment is discontinued. Available data and literature do not provide detailed insight into responder rates beyond the first application of high-concentration capsaicin patch.

[0022] A need exists for pharmaceutical agents useful for treating neuropathic conditions, preferably neuropathic pain, more preferably peripheral neuropathic pain, that overcome the shortcomings of the prior art. In particular, it would be desirable to make topical treatment of peripheral neuropathic pain with capsaicin available to patients who initially do not respond to high-concentration capsaicin topical dosage units, such as high-concentration topical patches or creams.

[0023] It is an object of the present invention to provide a pharmaceutical agent that is useful for the treatment of pain, preferably for the local treatment of neuropathic pain, and that has advantages over the prior art.

[0024] This object has been achieved by the subject matter of the present patent claims. Summary of the Invention

[0025] A first aspect of the present invention is and one or more high concentration capsaicin and / or capsaicinoid topical dosage units containing capsaicin and / or capsaicinoid, preferably at a concentration of at least 2.5% by weight, preferably at least 5% by weight, based on the total weight of the dosage unit; or one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches containing capsaicin and / or capsaicinoid, preferably at a concentration of at least 2.5% by weight, preferably at least 5% by weight, based on the total weight of the patch without a release liner; one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid in a concentration of at least 2.5% by weight, preferably at least 5% by weight, based on the total weight of the dosage unit, for use in the treatment of neuropathic conditions, preferably neuropathic pain, in which the patient did not perceive at least 30% pain relief relative to the total weight of the patch without a release liner;

[0026] In a preferred embodiment, the present invention comprises: one or more high concentration capsaicin topical dosage units comprising capsaicin, preferably at a concentration of at least 2.5% by weight, preferably at least 5% by weight, based on the total weight of the dosage unit; one or more high concentration capsaicin pharmaceutical patches comprising capsaicin, preferably at a concentration of at least 2.5% by weight, preferably at least 5% by weight, based on the total weight of the patch without a release liner; one or more high concentration capsaicin topical dosage units comprising capsaicin, preferably at a concentration of at least 2.5% by weight, preferably at least 5% by weight, based on the total weight of the patch without a release liner;

[0027] One or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention are for use in treating neuropathic conditions, preferably neuropathic pain, more preferably peripheral neuropathic pain. Further preferred aspects of treating neuropathic conditions according to the present invention involve regeneration and / or restoration of sensory nerve fibers, conversion of non-responders to prior topical administration of capsaicin and / or capsaicinoids to responders, increasing pain relief by more than 30% compared to baseline, etc.

[0028] Surprisingly, it has been found that by continuing (for example, repeatedly) topical administration of capsaicin to patients who do not respond adequately or do not respond to the initial topical administration of capsaicin (initial non-responders), these patients become responsive to capsaicin treatment over time, i.e., convert from initial non-responders to responders.Therefore, it has been found that, surprisingly, despite initial non-response, continuing topical administration of capsaicin thereby achieves improvement in the neuropathic condition that the patient suffers from, and in particular achieves relief from neuropathic pain.

[0029] Repeated application to initial non-responders provides additional benefit to patients. Across clinical trials, repeated treatment with high-concentration capsaicin dosage units (patches) converted more than one-third of initial non-responders into responders. At 12 months, the responder rate for patients who initially did not or did not adequately respond to high-concentration capsaicin and / or capsaicinoid dosage units (patches) was approximately 10% lower than the overall population, but the significantly increased responder rate for initial non-responders justifies repeated treatment.

[0030] Furthermore, additional data indicate that patients who have a poorer initial response and receive a second application sooner (i.e., with a treatment interval <84 days) will benefit proportionately more from the second application than patients who have a better initial response and are later retreated.

[0031] For capsaicin to exert its effects, TRPV1 receptors must be functional. If a nerve does not express functional TRPV1 receptors, capsaicin logically cannot exert its effects. Therefore, it can be reasonably assumed that in a subset of patients who do not respond to capsaicin, these receptors are not sufficiently functional to generate a response. Consequently, it is surprising that nerves that do not express fully functional TRPV1 receptors can be transformed into nerves that express fully functional TRPV1 receptors after the first or second application of capsaicin, even if this application is not successful during the first or second administration, in order to activate the receptors in a way that can produce a clinical response. DETAILED DESCRIPTION OF THE INVENTION

[0032] One or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the present invention contain capsaicin {i.e., (E)-8-methyl-N-vanillyl-6-nonenamide, trans-8-methyl-N-vanillyl-6-nonenamide, 6-nonenamide, (E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl} and / or one or more capsaicinoids. Capsaicin itself is sometimes considered a capsaicinoid. However, for purposes of this specification, capsaicin is not a capsaicinoid.

[0033] For purposes of this specification, "capsaicin and / or capsaicinoids" means either (i) capsaicin, or (ii) capsaicinoids, or (ii) capsaicin and capsaicinoids, but in each case the capsaicinoid may be a single capsaicinoid or any combination of capsaicinoids with each other. Unless otherwise specified, all weights and percentages refer to the total amount of all capsaicin and / or capsaicinoids present.

[0034] Capsaicinoids are known to those skilled in the art and are commercially available. Preferred capsaicinoids according to the present invention include, but are not limited to, zucapsaicin (ciscapsaicin, civamide), (6,7-)dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin I, nordihydrocapsaicin II, homocapsaicin I, homocapsaicin II, homodihydrocapsaicin I, homodihydrocapsaicin II, nornorcapsaicin, nornordihydrocapsaicin, octanoylvanillylamide, nonanoylvanillylamide (nonivamide), decanoylvanillylamide, and mixtures thereof.

[0035] Capsaicin and capsaicinoids are N-acyl derivatives of vanillylamine with different acyl chains R, as shown below: [ka]

[0036] [Table 1]

[0037] In a preferred embodiment, one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably high concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the present invention comprise capsaicin but are essentially free of capsaicinoid.

[0038] For purposes of this specification, a "dose unit" is defined as a predetermined amount of a pharmaceutical formulation containing a high concentration of capsaicin and / or capsaicinoids for topical application to a patient's skin.

[0039] For example, if the pharmaceutical formulation is a cream provided in a dispensing device (e.g., a tube), a dosage unit according to the present invention can be, for example, a strand of cream of a predetermined length obtained from the dispensing device. The strand of cream of a predetermined length contains a predetermined dose of capsaicin and / or capsaicinoid, which is administered locally to the patient when the strand of cream is applied to and spread over the patient's painful skin. Those skilled in the art will appreciate that various topical systems, such as creams, gels, ointments, and other liquid or semi-solid formulations, can be administered in doses of, for example, μg / cm 2 It is recognized that the capsaicin and / or capsaicinoid may be applied to the skin at various thicknesses, such that the applied dose per area of ​​skin, expressed as a percentage of the total applied dose, may vary. However, because the dosage unit is typically applied to the skin for a relatively short application period, e.g., 15 to 90 minutes, preferably 30 to 60 minutes, before it is removed, these potential thickness variations typically do not significantly alter the administered dose of capsaicin and / or capsaicinoid. Typically, less than 100% of the capsaicin and / or capsaicinoid originally contained in the dosage unit is administered within such a relatively short application period, while a significant amount of the capsaicin and / or capsaicinoid is removed with the remainder of the dosage unit at the end of the application period.

[0040] Similarly, when the pharmaceutical formulation is provided in the form of a topical patch, the dosage unit according to the present invention can be a patch that is arbitrarily cut to match the size and shape of the treatment area, containing a predetermined dose of capsaicin and / or capsaicinoid, which is locally administered to the patient when the patch is applied to the patient's painful skin.

[0041] Regardless of the type of pharmaceutical formulation (e.g., cream, gel, ointment, or patch), one or more topical dosage units according to the present invention contain a relatively high concentration of capsaicin and / or capsaicinoid of at least 2.5% by weight, preferably at least 5% by weight, more preferably at least 6.0% by weight, more preferably at least 7.0% by weight, and most preferably at least or about 8.0% by weight, based on the total weight of the dosage unit.

[0042] For purposes of this specification, unless otherwise specified, a "high concentration capsaicin and / or capsaicinoid topical dosage unit" refers to a dosage unit containing capsaicin and / or capsaicinoid at a concentration of at least 2.5% by weight, preferably at least 5% by weight, preferably at least or about 8% by weight, based on the total weight of the dosage unit and based on the total amount of capsaicin and / or capsaicinoid.

[0043] Preferably, high concentration capsaicin and / or capsaicinoid topical dosage units according to the present invention provide capsaicin and / or capsaicinoid in an amount that, when applied to a patient's skin in the manner for which the topical dosage unit is formulated, results in an application area concentration of 1000 mg / kg or more per 1000 mg of capsaicin and / or capsaicinoid per 1000 mg / kg of capsaicin and / or capsaicinoid per 1000 mg of capsaicin 2 at least 400 micrograms of capsaicin and / or capsaicinoids per cm of topical dosage unit, more preferably 2 At least 500 micrograms of capsaicin and / or capsaicinoids per cm of topical dosage unit, and even more preferably 2 At least 600 micrograms of capsaicin and / or capsaicinoids per cm of topical dosage unit, most preferably 2 The capsaicin and / or capsaicinoids may be present in an amount such that the capsaicin and / or capsaicinoids are at least or about 640 micrograms per serving.

[0044] The high concentration capsaicin and / or capsaicinoid topical dosage unit according to the present invention is not particularly limited and can be any topical system.

[0045] According to Appendix A of the FDA Guidance for Industry, Product Title and Initial USA approval in the Highlights of Precribing Information for Human Prescription Drug and Biological Products—Content and Format, January 2018, the term "system" is used for drug-containing delivery systems that control the release rate of the drug product from the system by diffusion kinetics, active transport, or other means. Activity is defined in terms of the release rate of the active ingredient(s) from the system over a specified period of time. The release rate and total duration of drug release are typically indicated on the drug product and container and carton labels, but not in the product title line. Exemplary systems include intrauterine systems, ocular systems, oral mucosal systems, periodontal systems, topical systems, transdermal systems, iontophoretic transdermal systems, and vaginal systems. The high-concentration capsaicin and / or capsaicinoid topical dosage units of the present invention are preferably "topical systems" according to this meaning.

[0046] Preferred topical dosage units (topical systems) according to the present invention include, but are not limited to, patches (e.g., matrix patches, drug-containing adhesive patches, iontophoresis systems), solutions, suspensions, lotions, ointments, creams, ointments, salves, pastes, gels (e.g., hydrogels, lipogels, poly(vinyl alcohol) semi-solid hydrogels), sprays, aerosols, foams, liposomal formulations (e.g., liposomal systems, liposphere systems, niosomal formulations, drug-containing cyclodextrin-in deformable liposomes), nanostructured formulations (e.g., nanostructured lipid carrier (NLC)-based gels, nanoemulgels), biodegradable drug platforms (e.g., composed of chitosan and guar gum), and the like.

[0047] In preferred embodiments, high concentration capsaicin and / or capsaicinoid topical dosage units according to the present invention are selected from aerosols (i.e., topical aerosols), creams, foams (i.e., topical foams), gels (i.e., topical gels), lotions, ointments, pastes, powders (i.e., topical powders), solutions (i.e., topical solutions), sprays (i.e., topical sprays), suspensions (i.e., topical suspensions), swabs, and systems (i.e., topical systems), preferably all in accordance with Appendix A of the FDA Guidance for Industry, Product Title and Initial USA approval in the Highlights of Prescribing Information for Human Prescription Drug and Biological Products—Content and Format, January 2018.

[0048] High-concentration capsaicin and / or capsaicinoid topical dosage units according to the present invention may be provided in the form of application aids such as impregnated gauze, impregnated wipes, impregnated sponges, impregnated fabrics (e.g., woven, nonwoven, knitted), etc. High-concentration capsaicin and / or capsaicinoid topical dosage units according to the present invention may be provided in the form of application or dispensing devices such as spray dispensers, foam dispensers, sticks, roll-ons, smooth-ons, etc. Low-concentration capsaicin roll-ons are commercially available, for example, under the trade names arth RX®, Reliaderm®, and mintedLeaf®.

[0049] A preferred high-concentration capsaicin and / or capsaicinoid topical dosage unit according to the present invention comprises capsaicin and / or capsaicinoid and one or more additives selected from hyaluronic acid, surfactants, penetration enhancers, and alcohol. Topical dosage units of this type are known from US 9,956,190, US 10,085,956, US 10,206,892, and US 10,583,100. Preferably, the hyaluronic acid is a mixture of two hyaluronic acids having different molecular weights, preferably a high molecular weight and a low molecular weight. Preferably, the surfactant is a nonionic surfactant, and the nonionic surfactant is preferably selected from polysorbates such as polysorbate 80, Cremophor® RH40 (polyoxy 40 hydrogenated castor oil), sorbitan esters (Spans), poloxamers, cetyl alcohol, cetostearyl alcohol, polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, stearyl alcohol, etc. Polysorbate 80 (PS80) and Polyox 40 hydrogenated castor oil are particularly preferred. Preferably, the penetration enhancer is selected from glycol monoethyl ether (DGME), propylene glycol, ethoxydiglycol, and dimethyl isosorbide. DGME and propylene glycol are particularly preferred. Preferably, the alcohol is selected from ethyl alcohol, benzyl alcohol, glycerol, propanol, isopropyl alcohol, polyethylene glycol, polyethylene glycol, etc. Ethyl alcohol (ethanol) is particularly preferred.

[0050] Preferably, a high concentration capsaicin and / or capsaicinoid topical dosage unit according to the present invention is a high concentration capsaicin and / or capsaicinoid pharmaceutical patch comprising capsaicin and / or capsaicinoid in a concentration of at least 2.5% by weight, preferably at least 5% by weight, more preferably at least 6.0% by weight, more preferably at least 7.0% by weight, and most preferably at least about 8.0% by weight, in each case based on the total weight of the patch without a release liner.

[0051] For purposes of this specification, unless otherwise specified, a "high concentration capsaicin and / or capsaicinoid pharmaceutical patch" refers to a pharmaceutical patch containing capsaicin and / or capsaicinoid at a concentration of at least 2.5% by weight, preferably at least 5% by weight, and preferably at least about 8% by weight, based on the total weight of the patch without a release liner.

[0052] Preferably, each of the one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches comprises a backing layer, an adhesive layer, and a release liner, and the capsaicin and / or capsaicinoid content is at least 2.5 wt.%, preferably at least 5 wt.%, more preferably at least 6.0 wt.%, even more preferably at least 7.0 wt.%, and most preferably at least about 8.0 wt.%, based on the total weight of the pharmaceutical patch without the release liner. Preferably, the capsaicin and / or capsaicinoid is contained in the adhesive layer (drug-containing adhesive).

[0053] For purposes of this specification, each high concentration capsaicin and / or capsaicinoid pharmaceutical patch includes a backing layer, an adhesive layer, and a release liner, and a high concentration capsaicin and / or capsaicinoid pharmaceutical patch having a capsaicin and / or capsaicinoid content of about 8.0% by weight, based on the total weight of the pharmaceutical patch without the release liner, is also referred to as an "8% capsaicin and / or capsaicinoid patch."

[0054] Preferably, one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches are provided within the cm of the patch. 2 At least 400 micrograms of capsaicin and / or capsaicinoids per cm of patch, more preferably 2 and even more preferably at least 500 micrograms of capsaicin and / or capsaicinoids per cm of patch. 2 At least 600 micrograms of capsaicin and / or capsaicinoids per cm of patch, most preferably 2The skin patch contains at least 640 micrograms of capsaicin and / or capsaicinoids per patch.

[0055] Preferably, one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches are provided with a cm 2 patch so that each patch contains a total of 179 mg of capsaicin and / or capsaicinoid. 2 Contains at least 640 micrograms of capsaicin and / or capsaicinoids per serving and contains 280 cm 2 The patch is a skin patch having an area of ​​14 cm x 20 cm. Preferably, each high-concentration capsaicin and / or capsaicinoid pharmaceutical patch comprises an adhesive side containing the active substance and an outer backing layer. The adhesive side is preferably covered with a removable release liner. Preferably, the adhesive side comprises a matrix containing capsaicin and / or capsaicinoid, silicone adhesive, diethylene glycol monoethyl ether, silicone oil, and ethylcellulose. Preferably, the outer backing layer comprises a polyethylene terephthalate film with a silicone-treated interior. Preferably, the removable protective layer (release liner) comprises a polyester film coated with a fluoropolymer. This type of high-concentration capsaicin pharmaceutical patch (8% capsaicin patch) is commercially available under the trade name Qutenza®.

[0056] Preferably, one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention are not permanently applied to a patient's skin, but rather are applied only for a relatively short period of time necessary to administer the capsaicin and / or capsaicinoid locally to the patient's skin from the one or more dosage units and patches, respectively. Administration is local, and penetration of the capsaicin and / or capsaicinoid is intradermal, preferably not systemic.

[0057] The one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, according to the present invention are preferably for single use.

[0058] When one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention are provided in the form of one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patches are preferably cut to match the size and shape of the treatment area. Preferably, the one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches are cut before removal of the release liner. When treating the feet, one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches are preferably wrapped around the dorsal, lateral, and plantar surfaces of each foot to completely cover the treatment area.

[0059] Preferably, one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention, are applied to the patient's skin for an application period of 15 to 90 minutes, preferably 30 to 60 minutes, and then removed.

[0060] Preferably, one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are applied to the most painful skin area (using up to four high-concentration capsaicin and / or capsaicinoid dosage units and high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, respectively). For purposes of this specification, "applying one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches to the skin" refers to the simultaneous or essentially simultaneous use of one, two, three, or four high-concentration capsaicin and / or capsaicinoid dosage units and high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, preferably one, two, three, or four 8% capsaicin and / or capsaicinoid patches, respectively. Because the area of ​​the patient's skin to be covered with the high concentration capsaicin and / or capsaicinoid pharmaceutical patch is greater than can be covered with a single high concentration capsaicin and / or capsaicinoid pharmaceutical patch, multiple high concentration capsaicin and / or capsaicinoid pharmaceutical patch patches may be required.

[0061] The painful area is preferably determined by a physician and marked on the skin. One or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, according to the present invention, are preferably applied to intact, non-irritating, dry skin and allowed to remain in place for 15 to 45 minutes, preferably 30 minutes, on the feet (e.g., for the treatment of HIV-associated neuropathy, painful diabetic peripheral neuropathy), and 45 to 75 minutes, preferably 60 minutes, on other locations (e.g., for the treatment of herpes neuralgia). In the case of high-concentration pharmaceutical patches, they are preferably first cut to match the size and shape of the painful area on the skin, and then applied to the skin.

[0062] For purposes of this specification, unless otherwise specified, "application period" preferably refers to a period of 15 to 90 minutes, preferably 30 to 60 minutes, during which one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention are applied to the patient's skin and then removed.

[0063] Application periods of less than 15 minutes and greater than 90 minutes are also contemplated in accordance with the present invention.

[0064] When the concentration of capsaicin and / or capsaicinoid in a high concentration capsaicin and / or capsaicinoid topical dosage unit (topical system) according to the present invention is particularly high, for example, greater than 8% by weight based on the total weight of the dosage unit, an application period of less than 15 minutes may be sufficient to topically administer the desired dose of capsaicin and / or capsaicinoid.

[0065] When the capsaicin and / or capsaicinoid concentration in a high-concentration capsaicin and / or capsaicinoid topical dosage unit (topical system) according to the present invention is particularly low, e.g., below 8% by weight based on the total weight of the dosage unit, an application period longer than 90 minutes may be required to topically administer the desired dose of capsaicin and / or capsaicinoid. Under these circumstances, some high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention having a capsaicin and / or capsaicinoid concentration below 8% by weight based on the total weight of the dosage unit are contemplated for repeated application over several consecutive days, with each dosage unit having an application period of 15 to 90 minutes, preferably 30 to 60 minutes. For example, it is contemplated that the assigned dose be applied for 60 minutes on each of four consecutive days.

[0066] The capsaicin and / or capsaicinoid contained in the high-concentration topical dosage unit (topical system) according to the present invention is intended for delivery to the skin. For any high-concentration topical dosage unit, the administered dose of capsaicin and / or capsaicinoid from the high-concentration topical dosage unit (topical system) is a function of the application period (application time), but depending on the individual formulation, the release rate may vary linearly over time. Individual release rates and other pharmacokinetic parameters can be determined by routine experiments (active substance dissolution and skin permeation assays) well recognized in the art. For example, in the case of Qutenza® capsaicin concentration 8% by weight, cm of patch 2 Based on in vitro studies using capsaicin (640 μg per 1000 μL), it is estimated that approximately 1% of capsaicin is absorbed into the epidermis and dermal layers of the skin during a 1-hour application (i.e., approximately 6.4 μg cm -2 ).

[0067] Preferably, the application period is such that the dose of capsaicin and / or capsaicinoid actually administered per area of ​​skin during the application period is at least 4.0 μg cm, depending on the individual characteristics of the high-concentration topical dose unit (type, concentration of capsaicin and / or capsaicinoid, excipients such as penetration enhancers, release rate, etc.). -2 , more preferably at least 4.5 μg cm -2 , and even more preferably at least 5.0 μg cm -2 , and even more preferably at least 5.5 μg cm -2 , most preferably at least 6.0 μg cm -2 is adjusted to be

[0068] After removing one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches from the skin, a cleansing gel is preferably applied in large quantities to the treatment area and left for at least 1 minute.The cleansing gel is then preferably wiped off with dry gauze to remove any remaining capsaicin and / or capsaicinoid from the skin.After wiping off the cleansing gel, it is preferable to gently wash the skin area with soap and water.A suitable cleansing gel may contain macrogol 300, carbomer, purified water, sodium hydroxide, edetate disodium, and butylhydroxyanisole.

[0069] Preferably, one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are applied to a patient's skin for an application period, remain on the skin, thereby locally administering capsaicin and / or capsaicinoid for the application period, and then removed, such that, as a result of the local administration of capsaicin and / or capsaicinoid by the one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient perceives pain relief of at least 30% relative to baseline, preferably on either a VAS or NRS pain rating scale, preferably on an NRS pain rating scale. It may take about 1 to 3 weeks from the application period for the analgesic effect to develop. Furthermore, repeated applications of one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention may be required until an initial non-responder is converted into a responder.

[0070] For example, topical administration is performed such that one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are preferably removed from the skin after an application period of 15 to 90 minutes, preferably 30 to 60 minutes. If so proceeded, treatment of a neuropathic condition, such as pain relief, as a result of the administered dose of capsaicin and / or capsaicinoid after removal from the skin may last for up to 90 days, or even longer.

[0071] Preferably, one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are applied to and remain on the patient's skin for an application period, thereby locally administering capsaicin and / or capsaicinoid for the application period, and then removed, such that, as a result of the local administration of capsaicin and / or capsaicinoid by the one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient perceives at least 30% pain relief relative to baseline, preferably for at least 4 weeks, more preferably at least 6 weeks, and even more preferably at least 8 weeks. Since it may take 1 to 3 weeks from the application period for the onset of the analgesic effect, the pain relief period does not necessarily begin immediately after the application period.

[0072] Subsequent applications of one or more additional high concentration capsaicin and / or capsaicinoid dosage units, preferably one or more additional high concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention may be repeated preferably after 2 to 4 months, preferably after 2 or 3 months, for example every 60 or 90 days.

[0073] In a preferred embodiment, subsequent applications of one or more other high concentration capsaicin and / or capsaicinoid dosage units, preferably one or more other high concentration capsaicin pharmaceutical patches according to the present invention, are repeated after 2 to 3 months, preferably after less than 90 days, more preferably after less than 84 days, even more preferably after 2 months, for example every 60 days. Subsequent applications of one or more other high concentration capsaicin and / or capsaicinoid dosage units according to the present invention may be repeated at shorter intervals, preferably less than 89 days, or less than 88 days, or less than 87 days, or less than 86 days, or less than 85 days, or less than 84 days, or less than 83 days, or less than 82 days, or less than 81 days; more preferably less than 80 days, or less than 79 days, or less than 78 days, in each case after the previous topical administration of capsaicin and / or capsaicinoid. It has been found that the response rate can be relatively increased when the treatment progresses to less than, or less than 77 days, or less than 76 days, or less than 75 days, or less than 74 days, or less than 73 days, or less than 72 days, or less than 71 days; and even more preferably less than 70 days, or less than 69 days, or less than 68 days, or less than 67 days, or less than 66 days, or less than 65 days, or less than 64 days, or less than 63 days, or less than 62 days, or less than 61 days, or less than 60 days.

[0074] In a particularly preferred embodiment, treatment may be repeated with subsequent applications every 90 days as warranted by persistence or recurrence of pain. Retreatment after less than 90 days is preferably considered for individual patients. Preferably, the minimum interval between treatments is 60 days.

[0075] For the purposes of this specification, two different preferred administration regimens are distinguished: According to a relatively fast administration regimen, hereinafter also referred to as "[f]", the period between two successive application periods is less than 90 days, preferably less than 84 days, more preferably about 2 months, e.g., 60 days; According to a relatively slow administration regimen, hereinafter also referred to as "s", the period between two successive application periods is about 3 months, for example 90 days.

[0076] Also, according to the present invention, it is contemplated that the period between two successive application periods can vary, and particularly can increase during the entire treatment period.For example, in a preferred embodiment, the period between the first application period and the second application period is less than 90 days, preferably less than 84 days, more preferably about 2 months, for example 60 days, while the subsequent period between the second application period and the third application period is about 3 months, for example 90 days.

[0077] It is also contemplated in accordance with the present invention that the time span between two successive application periods may be determined by the patient taking into account their individual pain perception.

[0078] When repeated applications are made, the one or more additional high concentration capsaicin and / or capsaicin system dosage units, preferably high concentration capsaicin and / or capsaicin system pharmaceutical patches, are preferably applied to the same painful area of ​​the patient's skin to which one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, have also been previously applied, i.e., 2 to 4 months prior.

[0079] Currently, the use of high-concentration topical capsaicin and / or capsaicinoids is not restricted in patients who do not initially respond to treatment, although improvement with repeated treatment has not currently been demonstrated in this patient subgroup.

[0080] According to the present invention, the patient's painful skin treatment area may be pre-treated with a local anesthetic (e.g., topical lidocaine (4%) or topical lidocaine (2.5%) / prilocaine (2.5%)) prior to application of one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, or the patient may be administered an oral analgesic (e.g., 50 mg tramadol) to reduce potential application-related discomfort. The local anesthetic is preferably applied to cover the entire treatment area and a 1-2 cm perimeter. The local anesthetic is preferably removed prior to application of one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches.

[0081] One or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, according to the present invention are for use in treating a neuropathic condition in a patient who, upon prior topical administration of capsaicin and / or capsaicinoid, has not perceived pain relief of at least 30% relative to baseline on either a VAS or NRS pain rating scale, preferably an NRS pain rating scale. Prior topical administration of capsaicin and / or capsaicinoid can be achieved primarily by any suitable pharmaceutical formulation capable of topically administering capsaicin and / or capsaicinoid. However, preferably, prior topical administration of capsaicin and / or capsaicinoid, achieved with one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention described herein, preferably an 8% capsaicin and / or capsaicinoid patch, has not previously been successful, as evidenced by the patient's failure to perceive at least 30% pain relief relative to baseline on either a VAS or NRS pain rating scale, preferably an NRS pain rating scale. Traditionally, in such situations, treatment is terminated due to lack of efficacy. However, according to the present invention, treatment is continued by re-administering one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention, preferably an 8% capsaicin and / or capsaicinoid patch, thereby converting the initial non-responder into a responder.

[0082] For purposes of this specification, patients who have not perceived at least 30% pain relief relative to baseline with prior topical administration of capsaicin and / or capsaicinoids are also referred to as "early non-responders."

[0083] Since the onset of pain relief may be delayed after topical administration of capsaicin and / or capsaicinoid, for example, after 1 to 3 weeks, by application of one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, preferably one or more 8% patches, pain relief relative to baseline is preferably determined after 4 weeks (28 days) of topical administration.

[0084] For purposes of this specification, consistent with existing literature and guidance, a "responder" is defined as a patient who achieves a 30% reduction from baseline in a numeric pain rating scale (NRS) or visual analogue scale (VAS). Conversely, a "non-responder" is defined as one who does not achieve a 30% reduction from baseline in such a rating scale. According to the present invention, the time point for measuring sustained therapeutic effect of chronic pain treatment may be 12 weeks. This time point is conventional and follows EMA pain guidance (15 December 2016 EMA / CHMP / 970057 / 2011 Committee for Medicinal Products for Human Use (CHMP)). However, it is common to assess pain more frequently, and therefore the time point at which a patient is assessed as a responder or non-responder is preferably 8 weeks after the prior topical administration of capsaicin and / or capsaicinoid.

[0085] Preferably, with respect to prior topical administration of capsaicin and / or capsaicinoid, the patient is an early non-responder selected from a complete non-responder and a poor responder.

[0086] For purposes herein, a "complete non-responder" is a patient who, upon prior topical administration of capsaicin and / or capsaicinoid, preferably, did not perceive any pain relief or even experienced a worsening of pain, preferably on the NRS pain rating scale, upon initial topical administration of capsaicin and / or capsaicinoid with one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention as described herein.

[0087] For purposes of this specification, a "poor responder" is a patient who, upon prior topical administration of capsaicin and / or capsaicinoid, preferably upon initial topical administration of capsaicin and / or capsaicinoid with one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention as described herein, perceived some pain relief, preferably on the NRS pain rating scale, but less than 30% compared to baseline.

[0088] According to the EMA Pain Guidance, referring to Koltzenburg M, McMahon S, Tracey I, Turk DC (eds.) Wall and Melzack's Textbook of Pain, 6th edition, Saunders, imprint of Elsevier Ltd., ISBN 978-0-7020-4059-7, pain intensity (PI) remains an important measure of analgesic efficacy. Among pain assessment scales, the visual analog scale (VAS), numeric rating scale (NRS), and verbal rating scale (VRS) are widely used and validated. The VAS is a continuous variable representing pain levels on a 10-cm line ranging from "no pain" to "extreme pain," while the NRS is a discrete variable representing pain levels ranging from 0 to 10 (JT Farrar et al. Pain 2001;94:149-58). Due to practical considerations, the latter is the most commonly used scale. The VRS, which consists of a series of verbal pain descriptors, has been shown to lack sensitivity for detecting changes in PI when compared with the VAS or NRS.

[0089] For purposes of this specification, a "responder" is defined as someone who reports a 30% reduction from baseline on either the VAS or NRS pain rating scale, preferably the NRS pain rating scale.

[0090] The preferred dosing regimens defined below typically involve the simultaneous and / or repeated application of one or more high concentration capsaicin and / or capsaicinoid dosage units, typically a single high concentration capsaicin and / or capsaicinoid pharmaceutical patch according to the present invention. Accordingly, to implement these preferred dosing regimens, multiple high concentration capsaicin and / or capsaicinoid dosage units, preferably multiple high concentration pharmaceutical patches, preferably multiple 8% capsaicin and / or capsaicinoid patches according to the present invention are used.

[0091] In a preferred embodiment, the patient treated according to the present invention has (ai) The patient may have a history of treatment in which one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, have been previously applied to the patient's skin for a first application period, thereby providing prior topical administration of capsaicin and / or capsaicinoid for the first application period, and then removed, whereby the patient did not perceive at least 30% pain relief relative to baseline (initial non-responder) as a result of the prior topical administration of capsaicin and / or capsaicinoid by the one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches.

[0092] Then, the prior topical administration under (ai) is not part of the use of one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, according to the present invention. The prior topical administration under (ai) merely qualifies the patient as an early non-responder. Those skilled in the art can easily determine, through medical history, whether a patient being treated is an early non-responder.

[0093] Preferably, (bi) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the first application period under (ai) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a second application period, thereby topically administering capsaicin and / or capsaicinoid during the second application period, and then removed; (b-ii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the second application period under (bi) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a third application period, thereby topically administering capsaicin and / or capsaicinoid during the third application period, and then removed; (b-iii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the third application period under (b-ii) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a fourth application period, thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and then removed; (b-iv) Optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the fourth application period under (b-iii) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a fifth application period, thereby administering capsaicin and / or capsaicinoid topically during the fifth application period, and then removed.

[0094] In a preferred embodiment, the patient treated according to the present invention has (ai) One or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, may be pre-applied to the patient's skin for a first application period, thereby pre-administering capsaicin and / or capsaicinoid topically for a first application period, and then removed, whereby the patient did not perceive at least 30% pain relief relative to baseline (initial non-responder) as a result of the pre-administration of capsaicin and / or capsaicinoid by the one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches.

[0095] Then, the prior topical administration under (ai) is again not part of the use of one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, according to the present invention. The prior topical administration under (ai) merely qualifies the patient as an early non-responder. Those skilled in the art can easily determine, through medical history, whether a patient being treated is an early non-responder.

[0096] Preferably, (bi) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the first application period under (ai) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a second application period, thereby topically administering capsaicin and / or capsaicinoid during the second application period, and then removed; Preferably, whereby, as a result of topical administration of capsaicin and / or capsaicinoid via one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient perceives at least 30% pain relief relative to baseline (responder), although the onset of at least 30% pain relief relative to baseline may occur with a delay of 1 to 3 weeks after the second application period; (b-ii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the second application period under (bi) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a third application period, thereby topically administering capsaicin and / or capsaicinoid during the third application period, and then removed; Preferably, thereby, as a result of topical administration of capsaicin and / or capsaicinoid by one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient still perceives at least 30% pain relief relative to baseline (responder), although the onset of at least 30% pain relief relative to baseline may occur with a delay of 1 to 3 weeks after the third application period, but preferably immediately follows the at least 30% pain relief relative to baseline achieved by the second application period described above under (bi).

[0097] In a preferred embodiment, the patient treated according to the present invention has (ai) One or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, may be pre-applied to the patient's skin for a first application period, thereby pre-administering capsaicin and / or capsaicinoid topically for a first application period, and then removed, whereby the patient did not perceive at least 30% pain relief relative to baseline (initial non-responder) as a result of the pre-administration of capsaicin and / or capsaicinoid by the one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches.

[0098] Then, the prior topical administration under (ai) is again not part of the use of one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, according to the present invention. The prior topical administration under (ai) merely qualifies the patient as an early non-responder. Those skilled in the art can easily determine, through medical history, whether a patient being treated is an early non-responder.

[0099] Preferably, (bi) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the first application period under (ai) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a second application period, thereby topically administering capsaicin and / or capsaicinoid during the second application period, and then removed; (b-ii) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the second application period under (bi) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a third application period, thereby topically administering capsaicin and / or capsaicinoid during the third application period, and then removed; Preferably, whereby, as a result of topical administration of capsaicin and / or capsaicinoid via one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient perceives at least 30% pain relief relative to baseline (responder), although the onset of at least 30% pain relief relative to baseline may occur with a delay of 1 to 3 weeks after the second application period; (b-iii) Optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the third application period under (b-ii) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and remain on the skin for a fourth application period, thereby providing a capsaicin and / or capsaicinoid for use in accordance with the fourth application period. The capsaicin and / or capsaicinoid is then topically administered and subsequently removed, preferably whereby, as a result of topical administration of capsaicin and / or capsaicinoid via one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient still perceives at least 30% pain relief relative to baseline (responder), although the onset of at least 30% pain relief relative to baseline may occur with a delay of 1 to 3 weeks after the fourth application period, but preferably immediately follows the at least 30% pain relief relative to baseline achieved by the third application period described above under (b-ii).

[0100] In a preferred embodiment, the patient treated according to the present invention has (ai) One or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, may be pre-applied to the patient's skin for a first application period, thereby pre-administering capsaicin and / or capsaicinoid topically for a first application period, and then removed, whereby the patient did not perceive at least 30% pain relief relative to baseline (initial non-responder) as a result of the pre-administration of capsaicin and / or capsaicinoid by the one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches.

[0101] Then, the prior topical administration under (ai) is again not part of the use of one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, according to the present invention. The prior topical administration under (ai) merely qualifies the patient as an early non-responder. Those skilled in the art can easily determine, through medical history, whether a patient being treated is an early non-responder.

[0102] Preferably, (bi) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the first application period under (ai) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a second application period, thereby topically administering capsaicin and / or capsaicinoid during the second application period, and then removed; (b-ii) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the second application period under (bi) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a third application period, thereby topically administering capsaicin and / or capsaicinoid during the third application period, and then removed; (b-iii) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the third application period under (b-ii) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a fourth application period, thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and then removed; Preferably, whereby, as a result of topical administration of capsaicin and / or capsaicinoid via one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient perceives at least 30% pain relief relative to baseline (responder), although the onset of at least 30% pain relief relative to baseline may occur with a delay of 1 to 3 weeks after the fourth application period; (b-iv) Optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the fourth application period under (b-iii) above, one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and remain on the skin for the fifth application period, thereby providing a sufficient amount of capsaicin and / or capsaicinoid during the fifth application period. The capsaicin and / or capsaicinoid is topically administered and subsequently removed, preferably whereby, as a result of topical administration of capsaicin and / or capsaicinoid via one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient still perceives at least 30% pain relief relative to baseline (responder), although the onset of at least 30% pain relief relative to baseline may occur with a delay of 1 to 3 weeks after the fifth application period, but preferably immediately follows the at least 30% pain relief relative to baseline achieved by the fourth application period described above under (b-iii).

[0103] In another preferred embodiment, the patient treated according to the present invention has not experienced at least 30% pain relief compared to baseline upon repeated prior topical administration of capsaicin and / or capsaicinoid, for example, after two consecutive prior topical administrations of capsaicin and / or capsaicinoid, or after three consecutive prior topical administrations of capsaicin and / or capsaicinoid (repeated non-responder). Preferably, the repeated prior topical administration of capsaicin and / or capsaicinoid, also achieved by one or more high-concentration capsaicin and / or capsaicinoid dosage units according to the present invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, has not previously been successful, such that the patient did not experience at least 30% pain relief compared to baseline, preferably on the NRS pain rating scale.

[0104] According to this embodiment, the patient to be treated according to the present invention is (ai) one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, are pre-applied to the patient's skin for a first application period, thereby pre-administering topical capsaicin and / or capsaicinoid for a first application period, and then removed, whereby the patient does not perceive at least 30% pain relief relative to baseline as a result of the pre-administration of capsaicin and / or capsaicinoid by the one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches; (a-ii) After the first application period under (ai) above, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, for example 60 days; or [s] about 3 months, for example 90 days, one or more high concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, are administered for a second application period. The patient may have a history of treatment in which the patient still did not perceive at least 30% pain relief relative to baseline as a result of prior topical administration of capsaicin and / or capsaicinoid by one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, previously applied to the patient's skin, thereby administering prior topical administration of capsaicin and / or capsaicinoid for a second application period, and then removed thereafter.

[0105] The prior topical administration under (ai) and (a-ii) above is then not part of the use of one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, according to the present invention. Repeating the prior topical administration under (ai) and (a-ii) simply qualifies the patient as a repeat non-responder. Those skilled in the art can easily determine whether a patient is a repeat non-responder in the course of a medical history.

[0106] Preferably, (bi) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the second application period under (a-ii), one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a third application period, thereby topically administering capsaicin and / or capsaicinoid during the third application period, and then removed; Preferably, whereby, as a result of topical administration of capsaicin and / or capsaicinoid via one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient perceives at least 30% pain relief relative to baseline (responder), although the onset of at least 30% pain relief relative to baseline may occur with a delay of 1 to 3 weeks after the second application period; (b-ii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, even more preferably 60 to 83 days, even more preferably about 2 months, e.g., 60 days; or [s] about 3 months, e.g., 90 days, after the third application period under (bi), one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use in accordance with the present invention, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, are applied to the patient's skin and left on the skin for a fourth application period, thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and then removed; Preferably, thereby, as a result of topical administration of capsaicin and / or capsaicinoid by one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient still perceives at least 30% pain relief relative to baseline (responder), although the onset of at least 30% pain relief relative to baseline may occur with a delay of 1 to 3 weeks after the fourth application period, but preferably immediately follows the at least 30% pain relief relative to baseline achieved by the third application period described above under (bi).

[0107] Preferred dosing regimens A to I are summarized in the table below: the prior use of one or more high concentration capsaicin and / or capsaicinoid dosage units according to the invention described herein, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, to the effect that the patient did not perceive pain relief of at least 30% relative to baseline; One or more high concentration capsaicin and / or capsaicinoid dosage units according to the invention described herein, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably an 8% capsaicin and / or capsaicinoid patch, have been used in treatment according to the invention with the effect that the patient perceives pain relief of at least 30% relative to baseline:

[0108] [Table 2]

[0109] In a preferred embodiment, when the administration regimen is relatively fast (i.e., [f]), in each instance, X is, independently of one another, 30 to 90, preferably 40 to 80, more preferably 50 to 70, and most preferably about 60. Preferably, X is, independently of one another, less than 90, more preferably less than 84, even more preferably 60 to 83. The X-day time intervals immediately follow one another without interruption. Similarly, in each instance, Y is, independently of one another, 30 to 90, preferably 40 to 80, more preferably 50 to 70, and most preferably about 60. The Y-day time intervals immediately follow one another without interruption.

[0110] In another preferred embodiment, when the dosing regimen is relatively slow (i.e., [s]), in each case, X is, independently of one another, 60 to 120, preferably 70 to 110, more preferably 80 to 100, and most preferably about 90. The X-day time intervals immediately follow one another without interruption. Similarly, in each case, Y is, independently of one another, 60 to 120, preferably 70 to 110, more preferably 80 to 100, and most preferably about 90. The Y-day time intervals immediately follow one another without interruption.

[0111] The above table provides information about the medical history of patients who have been previously treated with capsaicin and / or capsaicinoids and are currently preferably treated according to the present invention (patient medical history, left portion of the table, (a-i), (a-ii), and (a-iii), respectively). Prior treatment is not part of the treatment according to the present invention, but qualifies the patient as an early or repeat non-responder. With respect to prior treatment, "X days" means that one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention described herein, more preferably 8% capsaicin and / or capsaicinoid patches, were previously applied to the patient's skin at the beginning of the X-day interval and remained on the skin for the duration of application (15-90 minutes, preferably 30-60 minutes) before being removed from the skin. For the remainder of the X-day interval, no dosage units or pharmaceutical patches according to the present invention described herein were applied to the patient's skin. Such prior treatment did not have the desired effect of achieving at least 30% pain relief versus baseline (initial or repeat non-responders).

[0112] Furthermore, the above table provides information regarding preferred regimens for treating patients according to the present invention (Treatment, right-hand portion of the table, (bi), (b-ii), and (b-iii) respectively). With respect to treatment according to the present invention, "day Y" means that one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention described herein, more preferably 8% capsaicin and / or capsaicinoid patches, should be applied to the patient's skin at the beginning of the Y-day interval during the course of treatment according to the present invention, and remain on the skin for the duration of application (15 to 90 minutes, preferably 30 to 60 minutes) before being removed from the skin. For the remainder of the Y-day interval, no dosage units or pharmaceutical patches according to the present invention described herein are applied to the patient's skin. Such treatment has the desired effect of achieving at least 30% pain relief relative to baseline (responders). Furthermore, with respect to treatment according to the present invention, "optionally, on day Y" means that after treatment under (bi), i.e., 90 days later, optionally, another treatment with one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the present invention described herein, more preferably an 8% capsaicin and / or capsaicinoid patch, can occur, but need not.

[0113] Preferred regimens according to the above table are selected from (ai)-(bi), (ai)-(bi)-(b-ii), (ai)-(bi)-(b-ii)-(b-iii); (ai)-(a-ii)-(bi), (ai)-(a-ii)-(bi)-(b-ii), (ai)-(a-ii)-(bi)-(b-ii)-(b-iii); (ai)-(a-ii)-(a-iii)-(bi), (ai)-(a-ii)-(a-iii)-(bi)-(b-ii), and (ai)-(a-ii)-(a-iii)-(bi)-(b-ii)-(b-iii).

[0114] As already mentioned, the prior topical administration of capsaicin and / or capsaicinoid is preferably achieved by applying one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, to the patient's skin for an application period, thereby pre-administering capsaicin and / or capsaicinoid topically for the application period, and thereafter removing the one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches from the skin. Similarly, repeated prior topical administration is preferably achieved by repeatedly applying one or more high-concentration capsaicin and / or capsaicinoid topical dosage units (topical systems) according to the present invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, to the patient's skin during the application period, thereby achieving repeated prior topical administration of capsaicin and / or capsaicinoid during the application period, and then removing the one or more high-concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches from the skin.

[0115] Preferably, the one or more high concentration capsaicin and / or capsaicin topical dosage units, preferably the previously used one or more high concentration capsaicin and / or capsaicin pharmaceutical patches, were of the same type as the one or more high concentration capsaicin and / or capsaicin topical dosage units, preferably the one or more high concentration capsaicin and / or capsaicin pharmaceutical patches for use in accordance with the present invention, more preferably 8% capsaicin and / or capsaicin patches.

[0116] The present invention also contemplates the use of capsaicin and / or capsaicinoids for the manufacture of one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches comprising capsaicin and / or capsaicinoid, more preferably 8% capsaicin and / or capsaicinoid patches, for treating neuropathic conditions, preferably neuropathic pain, in patients who, upon prior topical administration of capsaicin and / or capsaicinoid, have not perceived pain relief of at least 30% relative to baseline, preferably on the NRS pain rating scale. Similarly, the present invention also contemplates a method for treating a neuropathic condition, preferably neuropathic pain, comprising applying to the skin of a patient who, upon prior topical administration of capsaicin and / or capsaicinoid, has not perceived pain relief of at least 30% relative to baseline, preferably on the NRS pain rating scale, one or more high concentration capsaicin and / or capsaicinoid topical dosage units, preferably one or more high concentration capsaicin and / or capsaicinoid pharmaceutical patches comprising capsaicin and / or capsaicinoid, more preferably an 8% capsaicin and / or capsaicinoid patch.

[0117] Preferably, the treatment of a neuropathic condition is for the relief of neuropathic pain, preferably peripheral neuropathic pain.

[0118] Preferably, the neuropathic pain is selected from the group consisting of painful diabetic neuropathy, post-herpetic neuralgia, chemotherapy-induced neuropathic pain, HIV-associated neuropathy, small fiber neuropathy, chronic idiopathic axonal polyneuropathy, post-traumatic neuropathic pain, and post-surgical neuropathic pain.

[0119] Preferably, the treatment of a neuropathic condition is for the regeneration and / or restoration of sensory nerve fibres.

[0120] Preferably, the treatment of the neuropathic condition is to convert a non-responder to a responder with respect to prior topical administration of capsaicin and / or capsaicinoids.

[0121] Preferably, the treatment of the neuropathic condition is for increasing pain relief by more than 30% relative to baseline, preferably at least 60% relative to baseline, preferably on the NRS pain rating scale. [Example]

[0122] The following examples further illustrate the present invention but should not be construed as limiting the scope of the invention.

[0123] In two selected trials with a 52-week duration, high-concentration capsaicin patches were applied to the feet for 30 minutes or to other body areas for 60 minutes. All patients were diagnosed with peripheral neuropathic pain. Initial non-responders were defined as patients with a <30% reduction in pain on the numeric pain rating scale from baseline to 3 months after baseline. Responders were defined as patients who achieved a ≥30% reduction in pain on the numeric pain rating scale at predefined time points (6 months, 9 months, and 12 months).

[0124] Example 1: All patients were diagnosed with non-diabetic peripheral neuropathic pain. Repeat treatment with Qutenza® was permitted every 9 to 12 weeks.

[0125] At 3 months, 76.6% (n = 306) of patients treated with high-concentration capsaicin patches did not meet responder criteria (n = 168). Of these 168, 115 patients (68%) were still on study treatment at 12 months. Of note, 174 patients (56.9%) from the original study population were still on study treatment at 12 months. Of the initial non-responders (n = 115), 57.3% had received at least four applications of high-concentration capsaicin patches. Overall, at 12 months, 33.9% of initial non-responders had become responders to treatment, while 43.7% of the total population could be classified as responders.

[0126] The results are summarized in the table below. In each case, only subjects who received a second application are included; *Time from first Qutenza® application to first Qutenza® reapplication. Percent change from baseline is summarized: if the baseline score was 10 and pain was reduced to 7 (on a 10-point NRS scale), the change from baseline would be -3, i.e., a % change from baseline of -30%. Mean is the average percent change from baseline for subjects in the sample. Median is the value indicating that half of the subjects had a % reduction below the indicated value and half of the subjects had a % reduction above the indicated value. Q1 and Q3 indicate that 25% and 75% of patients had values ​​below the % reduction value, respectively. Min-max is the maximum and minimum reduction (or maximum increase, if the value is positive). 95% CI is the 95% confidence interval around the mean.

[0127] [Table 3-1]

[0128] [Table 3-2]

[0129] [Table 4-1]

[0130] [Table 4-2]

[0131] [Table 5-1]

[0132] [Table 5-2]

[0133] [Table 6-1]

[0134] [Table 6-2]

[0135] [Table 6-3]

[0136] [Table 6-4]

[0137] [Table 6-5]

[0138] [Table 7-1]

[0139] [Table 7-2]

[0140] [Table 7-3]

[0141] [Table 7-4]

[0142] [Table 7-5]

[0143] Example 2: All patients were diagnosed with painful diabetic peripheral neuropathy. Repeated treatments with Qutenza® were permitted with at least an 8-week interval between treatments.

[0144] At 3 months, 48.6% (n = 313) of patients initially treated with high-concentration capsaicin patches did not meet responder criteria (n = 152). Of these 152 patients, 127 (i.e., 83.5%) were still on study treatment at 12 months, compared with 250 (79.9%) of the total population. Among initial non-responders receiving repeated applications, 80.2% had received at least four applications at 12 months. At 12 months, 45.7% of initial non-responders (n = 127) who were still on study treatment had responded to treatment, whereas 58% of the total population could be classified as responders. The 58% figure refers to the total population at 12 months, taking into account that not all patients remained on study for the full 12 months and that some patients may have lost response over time.

[0145] Further investigation into the optimal repeat treatment interval showed that the percentage of subjects who responded (defined as a 30% reduction from baseline in the Numerical Pain Rating Scale (NRS)) after the first application was lower (21.6%) in subjects with shorter treatment intervals (<84 days) compared with other subgroups with treatment intervals of ≥84 to <110 days or ≥110 days, with responder rates of 26.9% and 42.3%, respectively. This indicates that the group with the shortest treatment interval contained a greater number of non-responders. In clinical practice, it is logical to regress patients with a smaller treatment benefit earlier (i.e., with a shorter interval between treatments) because delaying treatment in such patients means they will suffer pain for a longer period of time. However, after the second application, the responder rates in the two groups with shorter treatment intervals (<84 days and ≥84 to <110 days) increased to 30.6% and 35.8%, respectively.

[0146] In other words, the responder rate was increased to 41.7% in patients with a treatment interval of <84 days compared with 33.1% in patients with an interval of <84 to 110 days. This result also supports that the responder rate can increase with repeated administration.

[0147] As demonstrated by Examples 1 and 2 above, repeated application to initial non-responders also provides additional benefit to patients. Over the course of the trial, more than one-third of the initial non-responders were converted to responders upon repeated treatment with high-concentration capsaicin patches. At 12 months, the responder rate for patients who initially did not respond to high-concentration capsaicin patches was approximately 10% lower than the overall population, but the significantly increased responder rate compared to >30% of patients who initially did not respond justifies repeated treatment.

Claims

1. 1. One or more high concentration capsaicin and / or capsaicinoid topical dosage units, comprising capsaicin and / or capsaicinoid in a concentration of at least 2.5% by weight based on the total weight of the dosage unit, for use in treating a neuropathic condition in a patient who has not perceived at least 30% pain relief relative to baseline upon prior topical administration of capsaicin and / or capsaicinoid.

2. 10. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 1, wherein the concentration of said capsaicin and / or capsaicinoid is at least 5% by weight based on the total weight of said dosage unit.

3. 3. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 1 or 2, wherein the concentration of said capsaicin and / or capsaicinoid is at least 8% by weight based on the total weight of said dosage unit.

4. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the patient's skin, whereby the patient perceives at least 30% pain relief relative to baseline.

5. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the skin of the patient, whereby the patient perceives at least 30% pain relief relative to baseline for at least 8 weeks.

6. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein the patient is selected from complete non-responders and poor responders with respect to prior topical administration of the capsaicin and / or capsaicinoid.

7. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the patient's skin for an application period of 15 to 90 minutes and then removed.

8. 8. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 7, wherein the application period is from 30 to 60 minutes.

9. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the patient's skin 2 to 4 months after a prior topical administration of capsaicin and / or capsaicinoid.

10. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 9, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the patient's skin less than 90 days, more preferably less than 84 days, even more preferably 60-83 days, even more preferably about 2 months, e.g., 60 days, after a prior topical administration of capsaicin and / or capsaicinoid [f].

11. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 9, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the patient's skin about 3 months, e.g., 90 days, after a prior topical administration of capsaicin and / or capsaicinoid.

12. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any one of the preceding claims, wherein the patient did not perceive at least 30% pain relief relative to baseline upon repeated prior topical administration of capsaicin and / or capsaicinoid.

13. 13. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 12, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the patient's skin 2 to 4 months after the last topical administration of the prior repetition of topical administrations.

14. 14. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 13, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the patient's skin less than 90 days, more preferably less than 84 days, even more preferably 60-83 days, even more preferably about 2 months, e.g., 60 days, after the last topical administration of the prior repeated topical administrations.

15. 14. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 13, wherein the one or more high concentration capsaicin and / or capsaicinoid topical dosage units are applied to the patient's skin about 3 months, e.g., 90 days, after the last topical administration of the prior repetition of topical administrations.

16. 10. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein a prior topical administration of capsaicin and / or capsaicinoid is achieved or a repeated prior topical administration is achieved by applying one or more high concentration capsaicin and / or capsaicinoid topical dosage units to the skin of said patient.

17. 17. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 16, wherein the one or more previously applied high concentration capsaicin and / or capsaicinoid topical dosage units were of the same type as the one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use.

18. the prior topical administration of capsaicin and / or capsaicinoid is achieved by applying one or more high concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid to the patient's skin for a first application period of 15 to 90 minutes, thereby pre-administering topical capsaicin and / or capsaicinoid during said first application period and thereafter removing said unit, whereby the patient does not perceive at least 30% pain relief relative to baseline; (b-i) 2 to 4 months after said first application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to said patient's skin and left on the skin for a second application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said second application period, and then removed; (b-ii) optionally, 2 to 4 months after said second application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to said patient's skin and left on the skin for a third application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said third application period, and then removed; (b-iii) optionally, 2 to 4 months after said third application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to said patient's skin and left on the skin for a fourth application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said fourth application period, and then removed; (b-iv) Optionally, 2 to 4 months after the fourth application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to the patient's skin and left on the skin for a fifth application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said fifth application period, and then removed.

19. (b-i) after said first application period [f] less than 90 days, more preferably less than 84 days, even more preferably 60-83 days, even more preferably about 2 months, e.g., 60 days, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to said patient's skin and left on the skin for a second application period of 15-90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said second application period, and then removed; (b-ii) optionally, [f] less than 90 days, more preferably less than 84 days, even more preferably 60-83 days, even more preferably about 2 months, e.g., 60 days, after said second application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to the patient's skin and left on the skin for a third application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said third application period, and then removed; (b-iii) optionally, after said third application period [f] less than 90 days, more preferably less than 84 days, even more preferably 60-83 days, even more preferably about 2 months, e.g., 60 days, one or more high concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to said patient's skin and left on the skin for a fourth application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said fourth application period, and then removed; (b-iv) optionally, after said fourth application period [f] less than 90 days, more preferably less than 84 days, even more preferably 60-83 days, even more preferably about 2 months, e.g., 60 days, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to the patient's skin and left on the skin for a fifth application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said fifth application period, and then removed.

20. (b-i) about three months, e.g., 90 days, after said first application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to said patient's skin and left on said skin for a second application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said second application period, and then removed; (b-ii) optionally, about 3 months, e.g., 90 days, after said second application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to said patient's skin and left on the skin for a third application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said third application period, and then removed; (b-iii) optionally, about three months, e.g., 90 days, after said third application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to said patient's skin and left on the skin for a fourth application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said fourth application period, and then removed; (b-iv) optionally, about 3 months, e.g., 90 days, after said fourth application period, one or more high concentration capsaicin and / or capsaicinoid topical dosage units comprising capsaicin and / or capsaicinoid are applied to the patient's skin and left on the skin for a fifth application period of 15 to 90 minutes, thereby topically administering capsaicin and / or capsaicinoid during said fifth application period, and then removed.

21. 10. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein each of said one or more high concentration capsaicin and / or capsaicinoid topical dosage units is a high concentration capsaicin and / or capsaicinoid pharmaceutical patch comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5% by weight, based on the total weight of the patch without a release liner.

22. 22. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 21, wherein the concentration of said capsaicin and / or capsaicinoid is at least 5% by weight, based on the total weight of the patch without a release liner.

23. 23. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 21 or 22, wherein the concentration of the capsaicin and / or capsaicinoid is at least 8% by weight, based on the total weight of the patch without a release liner.

24. 24. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of claims 21 to 23, wherein each high concentration capsaicin and / or capsaicinoid pharmaceutical patch comprises a backing layer, an adhesive layer, and a release liner, and the content of capsaicin and / or capsaicinoid is at least 6.0% by weight, based on the total weight of the pharmaceutical patch without the release liner.

25. 25. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 24, wherein the capsaicin and / or capsaicinoid content is about 8.0% by weight, based on the total weight of the pharmaceutical patch without a release liner.

26. Each high concentration capsaicin and / or capsaicinoid pharmaceutical patch comprises a cm ２ 26. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of claims 21 to 25, comprising capsaicin and / or capsaicinoid at a content of at least 400 μg of capsaicin and / or capsaicinoid per unit.

27. The content is ２ 27. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 26, wherein the high concentration capsaicin and / or capsaicinoid topical dosage units are about 640 micrograms of capsaicin and / or capsaicinoid per unit.

28. 10. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein each of said one or more high concentration capsaicin and / or capsaicinoid topical dosage units is a high concentration capsaicin topical dosage unit.

29. 10. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein said treatment of said neuropathic condition is for the relief of neuropathic pain.

30. 30. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 29, wherein said neuropathic pain is peripheral neuropathic pain.

31. 31. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to claim 29 or 30, wherein the neuropathic pain is selected from the group consisting of painful diabetic neuropathy, post-herpetic neuralgia, chemotherapy-induced neuropathic pain, HIV-associated neuropathy, small fiber neuropathy, chronic idiopathic axonal polyneuropathy, post-traumatic neuropathic pain, and post-surgical neuropathic pain.

32. 10. The one or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein said treatment of said neuropathic condition is for the relief of neuropathic pain selected from the group consisting of post-herpetic neuralgia, chemotherapy-induced neuropathic pain, HIV-associated neuropathy, small fiber neuropathy, chronic idiopathic axonal polyneuropathy, post-traumatic neuropathic pain, and post-surgical neuropathic pain.

33. 10. One or more high concentration capsaicin and / or capsaicinoid topical dosage units for use according to any of the preceding claims, wherein said treatment of said neuropathic condition is for the regeneration and / or restoration of sensory nerve fibres.

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