BR102016030392A2 - topical pharmaceutical composition, use and method of pain management - Google Patents

Abstract

The present invention relates to a topical pharmaceutical composition comprising ketamine or a pharmaceutically acceptable salt thereof, clonidine or a pharmaceutically acceptable salt thereof, or combinations thereof, useful in the prevention and treatment of acute and chronic pain, preferably neuropathic pain.

Description

(54) Title: TOPICAL PHARMACEUTICAL COMPOSITION, USE AND PAIN TREATMENT METHOD (51) Int. Cl .: A61K 31/4168; A61K 31/135; C07D 233/44; C07C 225/20; A61P 25/00 (73) Holder (s): CRISTÁLIA PRODUTOS QUÍMICOS FARMACÊUTICOS LTDA (72) Inventor (s): OGARI DE CASTRO PACHECO; ROBERTO CARLOS DEBOM MOREIRA; JORGE BARROS AFIUNE; MARISA DUTRA RODRIGUES RIZZI (74) Attorney (s): DOUGLAS VIEIRA PINTO (57) Abstract: The present invention relates to a topical pharmaceutical composition comprising ketamine or a pharmaceutically acceptable salt thereof, clonidine or a pharmaceutically acceptable salt thereof, or combinations thereof of these, useful in the prevention and treatment of acute and chronic pain, preferably neuropathic pain.

1/33 “TOPICAL PHARMACEUTICAL COMPOSITION, USE AND METHOD OF TREATING PAIN” [001] The present invention relates to the field of analgesia, prevention and treatment of pain. In particular, the present invention relates to a topical pharmaceutical composition comprising ketamine or a pharmaceutically acceptable salt thereof, clonidine or a pharmaceutically acceptable salt thereof, or combinations thereof, useful in the prevention and treatment of acute and chronic pain, preferably neuropathic pain.

State of the art [002] Pain is a symptom of many clinical disorders and affects a large part of the population. It is generally responsible for a significant part of the demand for health services and constitutes a multifactorial phenomenon involving psychosocial, behavioral and pathophysiological processes.

[003] According to the International Association for the Study of Pain (IASP), pain is characterized as an unpleasant sensory and emotional experience caused by real or potential tissue damage, or outlined in terms of such injury. Physiologically it works as an important warning sign triggering reactions of defense and preservation.

[004] From a clinical point of view, pain is classified according to its duration or evolution, which can be: acute or chronic. Acute pain has a physiological character, is triggered by tissue damage and has an alert and defensive function, mediated by thermal, mechanical or chemical stimulus of pain receptors. It is usually of short duration and can be of two types: neurogenic, when caused by peripheral nociceptive stimulus, or inflammatory, when caused by an inflammatory reaction. Therefore, acute pain has a well-defined cause-and-effect relationship, being characterized by being punctual, delimited, and by disappearing with the resolution of the pathological process.

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2/33 [005] Chronic pain, on the other hand, is gradually disabling, as it can persist for a long period of time, and in some cases it is related to the alteration of central nociception mechanisms. It can exist or persist in the absence of real injury, it produces persistent changes in psychomotor (emotional) behavior and can lead to permanent physical and mental disability.

[006] The most common chronic pains include cancer pain, myofascial pain syndrome, headache, fibromyalgia, pain associated with rheumatoid arthritis, phantom limb pain, central painful syndromes and neuropathic pain.

[007] Neuropathic pain can be defined as pain that arises as a direct consequence of an injury or disease that affects the somatosensory system and can be of central or peripheral origin, depending on the location of the affected nervous system. It is complex and heterogeneous, with signs and symptoms that can vary in intensity over time, and is often described as having a continuous or pungent burning character and being associated with allodynia and / or hyperalgesia. It is a debilitating condition, with a serious negative impact on the individual's quality of life, which often reports significant interference of this pain in daily activities.

[008] Due to their different pathophysiological mechanisms, agents useful in the treatment of other types of pain have reduced efficacy in the treatment of neuropathic pain, and the rate of non-responders to pharmacological treatment can be relatively high (Hansson PT, Attal N, Baron R, Cruccu G. Toward a definition of pharmacoresistant neuropathic pain. Eur J Pain. 2009; 13: 439-440). Therapeutic guidelines from different countries (Dworkin RH1, O'Connor AB, Audette J, Baron R, Gourlay GK, Haanpaa ML, Kent JL, Krane EJ, Lebel AA, Levy RM, Mackey SC, Mayer J, Miaskowski C, Raja SN, Rice AS, Schmader KE, Stacey B, Stanos S, Treede RD, Turk DC, Walco

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3/33

GA, Wells CD. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010; 85 (Suppl.): S3-S14) recommend the use of antidepressants and anticonvulsants for the management of neuropathic pain, opioids being generally recommended only as second or third line therapy. The search for the most appropriate drug for the case depends on the long-term follow-up of patients and individualized therapeutic responses.

[009] Important mechanisms for the development of chronic neuropathic pain include phosphorylation and positive regulation of N-methyl-D-aspartate (NMDA) receptors, loss of descending inhibition, plastic changes in the spinal cord and activation of immune cells in the spinal cord spinal cord with release of pro-inflammatory cytokines.

[010] Chronic pain syndromes resistant to conventional therapies have been treated in the last decades with subanesthetic doses of ketamine, an NMDA receptor antagonist, especially neuropathic chronic pain syndromes (Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-Daspartate receptors (J Pharmacol Exp Ther 1992; 260: 1209-13). The positive effects observed in this practice made the use of ketamine more frequent, especially associated with benzodiazepines and / or alpha2 adrenoceptor agonists, which minimize their adverse psychotropic effects (induction of psychedelic state, agitation, hallucination, nausea, and panic attacks) .

[011] Despite its ability to relieve chronic neuropathic pain, there is no consensus on the administration protocol. Generally administered systemically (infusions), ketamine has a short-acting analgesic effect (during infusion and a few hours after treatment) and is associated with adverse effects, often dependent, and problems with tolerance and / or interaction

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4/33 metabolic (Kalso E. The vicious circle in chronic pain management: balancing efficacy and adverse effects Curr Med Res Opin. 2011; 27: 2069-2071).

[012] Topical medications are, in general, well tolerated and, therefore, constitute a valuable option for the local treatment of neuropathic pain. Since the recognition of NMDA receptors in afferent sensory nerve endings in the mid-1990s, ketamine has been administered locally through topical application of gels and creams, and more recently, through oral solutions and local injections. When administered peripherally, ketamine is expected to reach higher concentrations in the target tissue than its systemic administration, amplifying its neuronal effects as well as its action on other cell types (keratinocytes, immune cells). Topical ketamine, when applied to patients with chronic neuropathic pain, is able to reduce allodynia and hyperalgesia, having been used in clinical practice to treat different types of pain (Jana Sawynok. Topical and Peripheral Ketamine as an Analgesic. Anesth Analg 2014; 119: 170-8; US5817699;

US5976547; US6017961; PI9912827-6; US6638981).

[013] In addition to NMDA receptors, there is evidence to indicate a potential importance of alpha-2 adrenergic receptors in neuropathic pain. In fact, the administration of α2 adrenergic agonists produces analgesia with potency comparable to that of morphine. Primary sensory neurons are rich in α2 adrenergic receptors located both in the dorsal root ganglion and in the gelatinous substance, where their stimulation inhibits glutamatergic neurotransmission, the main responsible for conducting pain information (Lavand'homme PM, Ma W, De Kock M, Eisenach JC. Perineural alpha (2A) -adrenoceptor activation inhibits spinal cord neuroplasticity and tactile allodynia after nerve injury. Anesthesiology. 2002. 97: 972-980).

[014] Clonidine, initially approved as an anti-petition drug 870160078604, of 12/22/2016, p. 21/51

5/33 hypertensive, it is an a2-adrenergic agonist that has shown efficacy for the treatment of acute and chronic pain, when administered by the intravenous, epidural or intrathecal routes (Eisenach JC, De Kock M, Klimscha W. a2-Adrenergic agonists for regional anesthesia. A clinical review of clonidine. Anesthesiology 1996; 85: 655-74). However, its systemic use (central action) is limited due to its adverse effects (sedation, dry mouth, hypotension / hypertension). Topical forms of administration have been developed to limit adverse events without, however, compromising their analgesic efficacy. Clinical and non-clinical studies have suggested that clonidine may be effective in relieving neuropathic pain when applied topically to the painful area (Campbell CM, Kipnes MS, Stouch BC, Brady KL, Kelly M, Schmidt WK, Petersen KL, Rowbotham MC, Campbell JN. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain. 2012. 153 (9): 1815-23; US5447947; US5993849, US6147102).

[015] The limited efficacy added to the toxic dose-limiting effects of the drugs available today, especially when administered systemically or in the neuroaxis, have made combination pharmacotherapy a common practice in search of better results for the management of neuropathic pain. In practice, it is common to associate different pharmacological agents with different mechanisms of action, such as opioid, non-opioid analgesics, antidepressants (duloxetine and amitriptyline), antiepileptics (gabapentin and pregabalin), 2-adrenergic agonists, anticonvulsants and local anesthetics ( Gilron I, Jensen TS, Dickenson AH., Combination pharmacotherapy for management of chronic pain: from bench to bedside. Lancet Neurol. 2013. 12: 1084-1095). Considering the multiterapies for pain treatment, the use of two or more drugs administered systemically increases the risk associated with the occurrence of side / adverse effects, since there are risks that the

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6/33 addition / synergy observed for its therapeutic effect also occurs for its adverse / side effects.

[016] Several studies have shown that the skin is an important target for treatments aimed at pain management, due to the presence of peripheral nociceptors, ligands and receptors in non-neural cells, as well as signaling between neural and non-neural cells. Studies have shown that the use of analgesics formulated as a combination for topical or transdermal administration leads to high concentration of drugs in the affected site, keeping systemic levels low, minimizing adverse side effects / side effects, increasing patient compliance to treatment and enabling action reversible pharmacological action can be reversed by removing anesthetic from the application site).

[017] As reported above, the presence of α2 adrenergic receptors and NMDA-like glutamatergic receptors on peripheral nociceptor endings, the occurrence of fine dendritic endings of nociceptor fibers in the dermis and epidermis layers, and evidence of the ketamine's antinociceptive action (especially dextrocetamine) and clonidine, alone, in neuropathic pain models, suggest the potential of the association of these two drugs in the control of peripheral neuropathic pain, especially through the administration of topical compositions.

[018] Ketamine has been administered topically in combination with other drugs (amitriptyline, baclofen, lidocaine, ketoprofen, clonidine, gabapentin, guanetidine;

(that of

WO2010036937; US6387957, US7820688, US7687080, US6638981, US2013123320, WO201348453), producing pain relief in 40% to 75% of the analyzes. The State of the Art reveals compositions for topical use containing the combination of ketamine and clonidine, in general with other drugs, where the use of clonidine is often suggested due to its ability to mitigate the adverse effects related to the use of antagonists of

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7/33 NMDA receptors (WO2010036937). The combination of the drugs ketamine and clonidine is suggested in the State of the Art, however there are no examples of compositions and embodiments that prove its therapeutic effect (US2005095277). In addition, controlled clinical studies do not confirm the reported results, showing that the concentration of assets and pharmaceutical formulation capable of promoting clinical efficacy for the treatment of neuropathic pain are not yet defined (Niesters M, Martini C., Dahan A., Ketamine for chronic pain: risks and benefits.British Journal of Clinical Pharmacology.

2014. 77 (2): 357-367).

[019] The effectiveness of topically administered combination therapies depends on the choice of combination and concentration of drugs, the vehicle, and the clinical condition of the patient. Suboptimal concentrations and suboptimal pharmaceutical properties of the vehicle contribute to the negative or null effects observed in some studies (Kopsky DJ, Keppel Hesselink JM, Bhaskar A., Hariton G., Romanenko V., Casale R. Analgesic effects of topical ketamine. Minerva Anestesiol .

2015. 81: 440-9; Jana Sawynok. Topical and Peripheral Ketamine as an Analgesic. 2014. Anesth Analg 119: 170-8).

[020] Resistance to drug permeation through the skin barrier (about 1-15% becomes bioavailable), the inherent instability of topical compositions (usually emulsions) containing anesthetics / analgesics (phase separation often occurs during storage) and recurrent oxidative instability for this class of drugs, make it difficult to reach therapeutically effective local concentrations after topical administration of these drugs.

[021] Transdermal creams and organogels predominate among the types of topical composition administered for the treatment of neuropathic pain. For example, US6197830 describes a lecithin-based composition for topical administration of the combination of an NMDA receptor antagonist and a tricyclic antidepressant (amitriptyline) and US5817699 and

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US6017961 describes the topical administration of ketamine in an organogel containing Pluronic and lecithin (PLO system). Other examples of topical lecithin-based compositions (in general, lecithin organogels - PLO) containing ketamine alone or in combination with other drugs, including clonidine are described: US7687080; US5817699; US5976547, US6730667; WO201348453.

[022] Studies indicate that repeated applications in the same place of topical compositions based on PLO can lead to systemic absorption of drugs, depending on the dose administered (Murdan S., A review of pluronic lecithin organogel as a topical and transdermal drug delivery system, Hospital Pharmacy, 2005. 12: 267 - 270). Although the availability of the drug in the bloodstream is the ultimate goal of several topical pharmaceutical compositions, in the case of analgesics / anesthetics such as ketamine and clonidine, ensuring its localized pharmacological action is essential to reduce the risks associated with its adverse / side effects widely known systemic drugs. In addition, in the case of chronic pain such as neuropathic pain, repetition of treatment in short periods of time is necessary, since, for most known drugs, a long-term therapeutic effect is hardly achieved.

[023] Although systemically the analgesic / anesthetic effect of clonidine and ketamine are directly related to the dosage, the therapeutic effect of these drugs when administered topically and in combination is still unknown, since the combinations disclosed in the State of the Art do not demonstrate nor suggest specific compositions and defined and effective concentrations for the treatment of localized neuropathic pain.

[024] Thus, although there is evidence of the topical analgesic action of the drugs ketamine and clonidine for the treatment of neuropathic pain, the compositions are little

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9/33 defined, have instabilities and often an absorption profile through the skin that is not adequate for an effective pharmacological action and restricted to peripheral nerve endings, avoiding the risks associated with known systemic side / adverse effects.

[025] Topical administration of analgesics / anesthetics for the treatment of chronic localized pain, especially neuropathic pain, is evidenced by the State of the Art as a promising form of treatment as long as the local action of the drugs is guaranteed. However, ensuring the effective and safe local action of drugs implies the definition of a composition that allows adequate skin permeability to achieve the desired therapeutic efficacy without, however, reaching plasma concentrations of the assets related to known adverse / side effects.

[026] In this context, the gift invention describe an topical composition understanding ketamine or one salt pharmaceutically acceptable this, clonidine or one salt pharmaceutically acceptable this, or combinations of these, for treatment of pain neuropathic, capable in ensure

therapeutically effective local concentrations of drugs and avoid their adverse / systemic side effects. The use of actives in the pharmaceutical composition described by the invention allowed to achieve the desired therapeutic efficacy even with the use of low concentrations of active ingredients. The low concentration of the assets associated with the ideal skin permeability guaranteed by the composition described in the present invention ensures the local action of the drugs, allowing greater safety of the formulation, thus avoiding the adverse / systemic side effects, without, however, reducing the effectiveness proposed treatment. In addition, the composition does not present acute / severe toxicity when applied topically and has excellent spreading on the skin, which increases patient compliance with treatment. Specifically, the present invention describes compositions useful in the treatment of

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10/33 neuropathic pain syndromes associated with: peripheral diabetic neuropathy (NDP), post-herpetic neuralgia (PHN), postoperative or post-traumatic peripheral neuropathy and leprosy.

[027] These and other advantages of the invention, as well as the additional inventive features combined with the same inventive concept, will be evident in the description of the invention provided in this document.

Summary of the invention [028] The present invention provides a topical pharmaceutical composition characterized by comprising ketamine or a pharmaceutically acceptable salt thereof in the concentration of 0.5% to 5% w / w and clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.01 % to 0.1% w / w. In addition, the topical pharmaceutical composition of the present invention is characterized by the fact that ketamine and clonidine, or a pharmaceutically acceptable salt thereof, are present in the proportion of 1: 0.03. Preferably, the topical pharmaceutical composition described by the present invention comprises 1% w / w of ketamine or a pharmaceutically acceptable salt thereof and 0.03% w / w of clonidine or a pharmaceutically acceptable salt thereof.

[029] In one embodiment, the present invention provides a topical pharmaceutical composition characterized in that it is in the form of an emulsion, preferably the topical composition is an emulsion-gel and even more preferably, the emulsion-gel comprises ketamine or a pharmaceutically acceptable salt thereof. , clonidine or a pharmaceutically acceptable salt thereof or combinations thereof. In a particular aspect, the topical composition is characterized by comprising ketamine or a pharmaceutically acceptable salt thereof in the concentration of 0.5% to 5% w / w, clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.01% to 0, 1% w / w or combinations of these. In addition, the topical pharmaceutical composition is

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11/33 characterized by the fact that ketamine and clonidine, or a pharmaceutically acceptable salt thereof, are present in the

proportion of 1 : 0.03. [030] In a aspect, the composition topical pharmaceutical is characterized for being a water / oil emulsion gel and understand: a) a matrix gel polymeric; B) one emulsifier fatty alcohol; ç) an lipophilic phase, d) one humectant; and) a preservative, f) one chelating agent, g) one

for understanding: a) keto-stearyl; c) neutralizing agent oil for pH adjustment and h) purified water. In a preferred embodiment of the invention, the topical composition is characterized by carboxypolymethylene; b) mineral alcohol and caprylic caprylic acid triglycerides, d) propylene glycol; e) parabens and phenoxyethanol, f) disodium edetate, g) a neutralizing agent for pH adjustment and h) purified water.

[031] Even more preferably, the topical pharmaceutical composition is characterized by comprising: a) carboxypolymethylene in the concentration of 1.5% w / w; b) ceto-stearyl alcohol at a concentration of 3.5% w / w; c) mineral oil and caprylic caprylic acid triglycerides at a concentration of 4.5% w / w; d) propylene glycol at a concentration of 5% w / w; e) parabens and phenoxyethanol at a concentration of 0.5% w / w; f) disodium edetate at a concentration of 0.05% w / w; g) a neutralizing agent for pH adjustment and h) purified water.

[032] The composition of the present invention demonstrates peripheral antinociceptive actions and absence of side / adverse effects. Induced analgesia is able to inhibit neuropathic pain and is significantly superior to the placebo group.

[033] Thus, the composition of the present invention is useful in the prevention and treatment of disorders or conditions in which pain predominates, including pains from particularly acute pain and chronic, neuropathic syndromes.

Specifically, the composition of the present invention is useful in

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12/33 prevention and treatment of neuropathic pain syndromes associated with: peripheral diabetic neuropathy; postherpetic neuralgia; postoperative peripheral neuropathy or post-traumatic peripheral neuropathy and leprosy.

[034] In a new aspect, the present invention describes the use of the described topical pharmaceutical composition characterized by the fact that it is in the manufacture of a medicament for the prevention and treatment of disorders or conditions in which pain predominates, including acute and chronic pain, particularly neuropathic pain. Specifically, the use of the composition of the present invention is characterized by the fact that it is in the manufacture of a medicament for the prevention and treatment of neuropathic pain syndromes associated with: peripheral diabetic neuropathy; post-herpetic neuralgia; postoperative peripheral neuropathy or post-traumatic peripheral neuropathy and leprosy.

[035] Additionally, the present invention describes a method of preventing and treating disorders or conditions in which pain predominates, including acute and chronic pain, particularly neuropathic pain, which comprises administering to an individual in need of said treatment an amount therapeutically effective use of the topical pharmaceutical composition according to the invention.

Brief Description of the Figures [036] The following describes the figures that accompany this specification, for a better understanding and illustration of the present invention.

[037] Figure 1. Individual pharmacokinetic profile of ketamine (broken lines). The solid line represents the mean profile ± SE (standard error). Sample size: 12 individuals.

[038] Figure 2: Experimental Design: Phase II / III, prospective, parallel, randomized, double-blind, placebo-controlled clinical study.

[039] Figure 3: Weekly evolution of the average pain assessed by the Visual Analogue Scale (VAS). It was considered 100% the

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13/33 value of the measurement taken before applying the first dose of medication.

[040] Figure 4: Pain evolution after 4, 8 and 12 weeks of treatment (Phase II / III clinical study). The graph represents the percentage of patients in each pain category, considering its intensity assessed by Visual Analogue Scale (VAS) every 4 weeks of treatment (S-4, S-8 and S12). B: baseline pain assessed before the first application. Classification (VAS): a) 0, “without pain”, VAS between 0 and 1 b) 1, “mild pain”, VAS between 1 and 3 c) 2, “moderate pain”, VAS between 3 and 5.4 d ) 3, “severe pain”, VAS between 5.4 and 10.

Definitions [041] To ensure a better understanding of the scope of the invention, without being a limiting factor, the technical terms of the related technology areas, as used in the present invention, are defined below.

[042] The term "ketamine" refers to the racemic mixture and its isolated R (+) and S (+) enantiomers.

[043] The term "therapeutically effective amount" refers to a sufficient amount of a compound or composition that induces a positive modification to a condition being treated, however low enough to avoid side / adverse effects. The therapeutically effective amount of a compound or composition can vary according to the age, physical and clinical conditions of the person to be treated, duration of treatment, among other factors common to a person skilled in the art.

[044] The term "pharmaceutically acceptable salt" includes, but is not limited to, metal salts or acid addition salts. The nature of the salt is not critical as long as it is pharmaceutically acceptable. Said salts can be obtained by conventional methods well known in the art.

[045] The term "individual" refers to humans and animals. Preferably the individual is a human being.

[046] The term “topical administration” refers to the

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14/33 administration of a composition comprising the drug on the skin in order to produce a local effect.

[047] The terms "prevent or treat" or "prevention or treatment", as used in the present invention, refer to reversing, relieving, inhibiting or decreasing pain in humans or animals.

[048] "The disorders or conditions in which pain predominates, including acute and chronic pains", as used in the present invention, are selected from the group, but not limited to it, which comprises osteoarticular and muscular injuries of traumatic origin, injuries of the nervous system of traumatic origin, and mechanical injuries, by radiation, surgical, thermal, chemical or electrical burns; pain due to cancer or non-cancer disease due to a somatic (eg nociceptive), neuropathic or psychogenic mechanism; osteoarthritis; postoperative pain; pain from neurodegenerative diseases, including amyotrophic lateral sclerosis; pain from neuropathies associated with degenerative diseases, including diabetes; pain due to metabolic changes, including diabetes mellitus, hypo or hyperthyroidism; pain due to Work-Related Musculoskeletal Disorder (D.O.R.T); pain due to infectious or parasitic diseases, including leprosy, herpes zoster, acquired immunodeficiency syndrome (AIDS); pain from deaferentation, phantom limb pain, complex regional pain syndrome type II, complex regional pain syndrome, amputation stump pain, reflex sympathetic dystrophy, post-herpetic neuralgia, diabetic mononeuropathy, polyarthritis nodosa, post-radiotherapy pain, polyneuropathies , multiple mononeuritis, infectious and neurodegenerative myelopathies, toxic neuropathies, vasculitis and syringomyelia.

[049] “Allodynia” refers to pain in response to a stimulus that normally does not cause pain (not harmful) and “hyperalgesia” refers to the exacerbated sensitivity to a stimulus that is

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15/33 painful (harmful).

[050] Emulsion-gel refers to emulsions, defined as heterogeneous preparations composed of two immiscible liquids [lipophilic (oily) phase and aqueous or hydrophilic phase] where one immiscible phase is dispersed in the other uniformly in the form of delicate drops stabilized by an emulsifying agent, to which a gel matrix is added, preferably of a polymeric nature.

[051] The term water-oil emulsion-gel ”refers to a stable emulsion in which the oil phase is the dispersion medium and the aqueous component is the dispersed phase over which a polymeric gel matrix is added.

[052] The objects of the present invention will be better understood from the detailed description of the invention and the attached claims.

Detailed description of the invention [053] The present invention relates to a pharmaceutical composition that can be applied topically to the skin for pain relief at the application site.

[054] The present invention relates to a topical pharmaceutical composition characterized by comprising ketamine or a pharmaceutically acceptable salt thereof in the concentration of 0.5% to 5% w / w and clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.01% 0.1% w / w. Preferably, the topical composition of the present invention comprises ketamine or a pharmaceutically acceptable salt thereof in the concentration of 1% to 2% w / w and clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.03% to 0.06% w / w.

[055] In addition, the present invention describes a topical pharmaceutical composition characterized by the fact that ketamine and clonidine, or a pharmaceutically acceptable salt thereof, are present in the proportion of 1: 0.03. Preferably, the topical pharmaceutical composition of the present invention comprises ketamine or a pharmaceutically salt

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16/33 of this at a concentration of 1% w / w and clonidine or a pharmaceutically acceptable salt thereof at a concentration of 0.03% w / w.

[056] Ketamine, an intravenous anesthetic with great analgesic potency, is a racemic mixture whose R (-) and S (+) enantiomers have comparable pharmacokinetic profiles, but different clinical effects. The anesthetic potency of the S (+) ketamine (dextrocetamine) isomer is about 3 times greater than that of R (-) ketamine (levocetamine) and its analgesic effect is approximately four times greater when compared to that of R (-) ketamine. Thus, preferably, the topical composition of the present invention is characterized by the fact that ketamine is S (+) ketamine (dextrocetamine).

[057] It is possible to use pharmaceutically acceptable salts here, for example, mineral acid salts, such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and salts of organic acids, such as acetates, propionates, malonates, benzoates, and the like. Thus, in a preferred embodiment, the topical pharmaceutical composition is characterized in that ketamine is dextrocetamine hydrochloride and clonidine is clonidine hydrochloride.

[058] In another aspect, the topical pharmaceutical composition is characterized by being in the form of an emulsion, preferably emulsion-gel.

[059] Thus, the topical pharmaceutical composition according to the present invention is characterized in that it is an emulsion-gel comprising ketamine or a pharmaceutically acceptable salt thereof, clonidine or a pharmaceutically acceptable salt thereof, or combinations thereof. In a particular aspect, the topical pharmaceutical composition is characterized by comprising ketamine or a pharmaceutically acceptable salt thereof in the concentration of 0.5% to 5% w / w, clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.01% to 0 , 1% w / w, or combinations thereof. Preferably, the composition

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Topical pharmaceutical 17/33 is characterized by comprising ketamine or a pharmaceutically acceptable salt thereof in the concentration of 1% to 2% w / w and clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.03% to 0.06% w / w. In addition, the topical pharmaceutical composition is characterized by the fact that ketamine and clonidine, or a pharmaceutically acceptable salt thereof, are present in the proportion of 1: 0.03. Even more preferably, the topical pharmaceutical composition is characterized by comprising ketamine or a pharmaceutically acceptable salt thereof at a concentration of 1% w / w and clonidine or a pharmaceutically acceptable salt thereof at a concentration of 0.03% w / w. Specifically, the topical pharmaceutical composition of the present invention is characterized in that ketamine is dextrocetamine hydrochloride and clonidine is clonidine hydrochloride.

[060] The topical composition according to the present invention is characterized by being a water / oil emulsion gel which comprises a gel matrix, emulsifiers, a lipophilic phase, humectants, chelating agents, neutralizers for pH adjustment, preservatives, water purified and other components that may benefit the skin and / or specific characteristics of the composition, including, but not limited to: conditioning agents, skin protectors, antioxidants, viscosity modifying agents, film forming agents, bioadhesive polymers, surfactants, fragrance , emulsion stabilizing agents, foaming and non-foaming agents, opacity agents, bulking agents, dyes, inert carriers, lipid and moisture absorbers, and a combination of these.

[061] In a particular aspect of the invention, the gel matrix is of a polymeric nature, preferably carboxypolymethylene.

[062] The gel matrix is present in the concentration of 0.5% to 3% by weight of the total weight of the composition (w / w). Preferably, the gel matrix is present at a concentration of 1.5% w / w.

[063] Emulsifiers within the scope of this

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18/33 invention can be cationic, anionic, nonionic or amphoteric. For use in the present invention, emulsifiers are any material or mixture of hydrophilic or hydrophobic materials accepted for topical administration and capable of stabilizing an emulsion. Emulsifiers include, but are not limited to: alkaline and ammonium soap, such as sodium stearate; divalent and trivalent metallic soap such as calcium oleate; Organic sulfates, including sodium lauryl sulfate; quaternary ammonium compounds, such as cetrimonium bromide; pyridinic compounds, for example, hexadecylpyridinium chloride; ethers of polyethylene glycol alcohols, including Ceteth 20; polyethylene glycol fatty acid esters, such as, for example, polyethylene glycol 40 stearate; ethoxylated fatty acids, such as sorbitan mono-oleate (Span 80); polyethylene glycol esters, including polyoxyethylene sorbitan monooleate (Tween 80); fatty alcohols, such as cetyl alcohol and cetostearyl alcohol; and fatty acids, such as stearyl acid; sterols, including cholesterol and its esters; and combinations of these.

[064] Preferably, the emulsifier of the described composition is a fatty alcohol. More preferably, the emulsifier of the composition of the present invention is ceto-stearyl alcohol. The emulsifier is present in the concentration of 2 to 5% by weight of the total weight of the composition (w / w). Preferably, the emulsifier is present at a concentration of 3.5% w / w.

[065] The lipophilic phase according to the present invention can be any water-insoluble (hydrophobic) organic material or mixture of materials that form a stable emulsion comprising ketamine and clonidine or pharmaceutically acceptable salts thereof. The lipophilic phase in the composition of the present invention, which also has the function of emollient, includes, but is not limited to: triglycerides which include, but are not limited to, vegetable and animal fats and oils such as palm oil,

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19/33 coconut oil, castor oil, cocoa butter, safflower oil, cottonseed oil, corn oil, olive oil, cod liver oil, avocado oil, almond oil, sesame oil, squalene , kikui oil and soy oil; esters of acetoglycerides, including but not limited to acetylated monoglycerides; Ethoxylated glycerides such as ethoxylated glyceryl monostearate; Alkyl fatty acid esters having 10 to 20 carbon atoms that include, but are not limited to, methyl, ethyl, isopropyl and butyl fatty acid esters; Alkenyl fatty acid esters having 10 to 20 carbon atoms such as oleyl myristate, oleyl stearate and oleyl oleate; Fatty acids with 10 to 20 carbon atoms such as pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidic, behenic and erucic acids; Fatty alcohols with 10 to 20 carbon atoms, such as lauryl, myristyl, cetyl, hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, beenyl, erucyl and 2-octyl dodecanyl; Lanolin and lanolin derivatives including, but not limited to, lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated cholesterol and lanolin alcohols; esters of polyhydric alcohol, including but not limited to, esters of ethylene glycol mono- and di-fatty acids, diethylene glycol and polyethylene glycol (200-6000); wax esters such as beeswax, spermaceti, myristyl myristate, stearyl stearate; beeswax derivatives including, but not limited to, polyoxyethylene sorbitol beeswax; vegetable waxes, including, but not limited to, carnauba and candelilla waxes; sterols including, but not limited to, cholesterol and cholesterol esters; amides such as fatty acid amides, ethoxylated fatty acid amides and solid fatty acid alkanolamides;

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20/33 aliphatic hydrocarbons obtained from petroleum as mineral oil; and combinations of these.

[066] In a preferred aspect, the lipophilic phase of the composition comprises the combination of aliphatic hydrocarbons derived from petroleum and medium chain triglycerides extracted from vegetable oils. Preferably, the composition comprises the combination of mineral oil and capric and caprylic acid triglycerides.

[067] The lipophilic phase is present at a concentration of 1.5% to 15% by weight of the total weight of the composition (w / w). Preferably, the lipophilic phase is present at a concentration of 4.5% w / w.

[068] Humectants include, but are not limited to: ammonium alginate; butylene glycol; cyclomethicone; glycerol; triacetin; urea, polydextrose; propylene glycol; sodium hyaluronate; sodium lactate; sorbitol; trehalose; xylitol; and combinations of these. Preferably, the humectant is propylene glycol.

[069] The humectant is present in the concentration of 3% to 15% by weight of the total weight of the composition (w / w). Preferably, it is present at a concentration of 5% w / w.

[070] Preservatives include, but are not limited to: phenoxyethanol; parabenzoates; chlorocresol; quaternary amines, such as benzalkonium chloride, cetrimide, benzethonium chloride; organic acids, such as sorbic acid, p-hydroxybenzoic acid and benzoic acid; Parabens, such as methyl paraben, ethyl paraben, propyl paraben and butyl paraben; alcohols, such as benzyl alcohol and isopropyl alcohol; phenols, such as triclosan, and thimerosal; hydantoin derivatives; chloromethylthiazoline; methylisothiazoline; hexetidine; chlorhexidine; imidazolidinyl urea and combinations of these. Preferably, the preservative of the composition of the present invention comprises a combination of parabens and phenoxyethanol.

[071] The preservative is present in the concentration of 0.01% at

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21/33

2% by weight of the total weight of the composition (w / w). Preferably, it is present in the concentration of 0.5% w / w. [072] Chelating agents may include, but are not limited to: malic acid; pentetic acid; citric acid monohydrate; disodium edetate; edetic acid; and combinations of these. Preferably, the chelating agent is disodium edetate. The chelating agent is present in the concentration of 0.005% to 0.1% by weight of the total weight of the composition (w / w). Preferably, it comprises 0.05% w / w.

[073] The neutralizing agent is present in the composition in sufficient quantity to adjust the pH between 4 and 7. Preferably, the neutralizing agent for pH adjustment is triethanolamine.

[074] Thus, in one aspect of the invention, the topical pharmaceutical composition is characterized by being a water / oil emulsion gel and comprising: a) a polymeric gel matrix; b) a fatty alcohol emulsifier; c) a lipophilic phase, d) a humectant; e) a preservative, f) a chelating agent, g) a neutralizing agent for pH adjustment and h) purified water.

[075] In particular, the topical pharmaceutical composition of the present invention is characterized by a) being carboxypolymethylene and b) being ceto-stearyl alcohol.

[076] More particularly the topical composition of the present invention is characterized by comprising: a) carboxypolymethylene; b) ceto-stearyl alcohol; c) mineral oil and capric and caprylic acid triglycerides, d) propylene glycol; e) parabens and phenoxyethanol, f) disodium edetate, g) a neutralizing agent for pH adjustment and h) purified water.

[077] Additionally, the topical composition is characterized by being a water / oil emulsion gel and comprising: a) a polymeric gel matrix in the concentration of 0.5% to 3% w / w; b) a fatty alcohol emulsifier in a concentration of 2% to 5% w / w; c) a lipophilic phase at a concentration of 1.5% to 15% w / w; d) a humectant in the concentration of 3% to 15% w / w; e) preservatives in

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22/33 concentration from 0.01% to 2% w / w; f) a chelating agent at a concentration of 0.005% to 0.1% w / w; g) a neutralizing agent for pH adjustment and h) purified water.

[078] Even more preferably, the topical composition is characterized by comprising: a) 1.5% w / w carboxypolymethylene; b) ceto-stearyl alcohol at a concentration of 3.5% w / w; c) mineral oil and capric and caprylic acid triglycerides at a concentration of 4.5% w / w; d) propylene glycol at a concentration of 5% w / w; e) parabens and phenoxyethanol at a concentration of 0.5% w / w; f) disodium edetate at a concentration of 0.05% w / w; g) a neutralizing agent for pH adjustment and h) purified water.

[079] In a particular scope, the topical pharmaceutical composition of the invention is characterized by the fact that mineral oil and capric and caprylic acid triglycerides are present in the proportion of 0.45 / 0.55.

[080] Specifically, the topical pharmaceutical composition of the present invention is characterized by comprising ketamine or a pharmaceutically acceptable salt thereof at a concentration of 1% w / w, clonidine or a pharmaceutically acceptable salt thereof at a concentration of 0.03% w / w. excipients: a) 1.5% w / w carboxypolymethylene; b) ceto-stearyl alcohol at a concentration of 3.5% w / w; c) mineral oil and capric and caprylic acid triglycerides at a concentration of 4.5% w / w; d) propylene glycol at a concentration of 5% w / w; e) parabens and phenoxyethanol at a concentration of 0.5% w / w; f) disodium edetate at a concentration of 0.05% w / w; g) a neutralizing agent for pH adjustment and h) purified water.

[081] The topical composition of the present invention can be prepared by conventional emulsion preparation techniques taught in the state of the art and known to a person skilled in the art. Preferably, the gel emulsion is prepared by the steps described below:

A - Add the emulsifier, the lipophilic phase, the humectant and the preservative to a homogenizer; keep the mixture at

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23/33 a maximum temperature of 80 ° C and mix;

B - Add purified water, homogenize and start cooling the mixture until a temperature between 60 ° C and 70 ° C is obtained;

C- Add the polymeric gel matrix and mix; keeping the mixture at a temperature between 60 ° C and 70 ° C;

D - Cool the mixture to a maximum temperature of 40 ° C;

E - Solubilize dextrocetamine hydrochloride, clonidine hydrochloride and the chelating agent in purified water and add the resulting solution to the homogenizer;

F - Add the neutralizing agent to adjust the pH in the range between 4 and 7 and homogenize;

G - Adjust the final weight with purified water and mix;

H - Deaerate and fill.

[082] The pharmaceutical composition described in the present invention must be administered topically to the skin by a medical professional or by the patient himself by simple mechanical friction at the application site or through an adhesive comprising the described composition.

[083] Additionally, the topical pharmaceutical composition described by the present invention is characterized by the fact that it is useful in the prevention and treatment of any indication resulting from harmful stimuli of peripheral neuroreceptors. Thus, the topical composition described by the present invention is characterized by the fact that it is useful in the prevention and treatment of disorders or conditions in which pain predominates, including acute and chronic pain. The pain may be of oncological or non-oncological origin, and result from a somatic, neuropathic or psychogenic mechanism. Acute pain can be neurogenic or inflammatory, and chronic pain can be neuropathic, like hyperalgesia or allodynia. Preferably, the composition is useful in the prevention and treatment of neuropathic pain syndromes. Specifically, the composition is useful in the prevention and treatment of neuropathic pain syndromes associated with: a) diabetic neuropathy

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24/33 pain to be treated can be inflammatory; of peripheral origin; b) post-herpetic neuralgia; c) postoperative peripheral neuropathy or posttraumatic peripheral neuropathy and, d) leprosy.

[084] In another embodiment, the invention relates to the use of the topical pharmaceutical composition of the present invention characterized by the fact that it is in the manufacture of a medicine for the prevention and treatment of disorders or conditions in which pain predominates, including acute and chronic pain. . The pain may be of oncological or non-oncological origin, and result from a somatic, neuropathic or psychogenic mechanism. Acute pain can be neurogenic or inflammatory, and chronic pain can be neuropathic, like hyperalgesia or allodynia. Preferably, the use of the pharmaceutical composition of the present invention is characterized by the fact that it is in the manufacture of a medicament for the prevention and treatment of neuropathic pain syndromes. Specifically, the use is characterized by the fact that it is in the manufacture of a medication for the prevention and treatment of neuropathic pain syndromes associated with: a) peripheral diabetic neuropathy; b) post-herpetic neuralgia; c) postoperative peripheral neuropathy or post-traumatic peripheral neuropathy and, d) leprosy. The use of the composition is also characterized by the fact that it is in the manufacture of a medicine for preemptive analgesia.

[085] In another aspect of the invention, there is provided a method of preventing and treating disorders or conditions in which pain predominates, including acute and chronic pain, characterized in that it comprises administering to a subject in need of said treatment a therapeutically effective dose topical composition as described in the present invention. To be: acute neurogenic or oncological or non-oncological pain;

due to a somatic, neuropathic or psychogenic mechanism; chronic neuropathic pain of the type hyperalgesia or allodynia. Preferably the pain is neuropathic.

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25/33 [086] The examples cited below are merely illustrative, and should be used only for a better understanding of the developments contained in the present invention, however, they should not be used in order to limit the objects described.

Example 1. Water / oil gel emulsion: 1% dextrocetamine hydrochloride and 0.03% clonidine hydrochloride.

[087] The topical composition of the present invention can be

illustrated by excipients and in table 1. Ingredients described assets Table 1. Example of composition topical of the present invention. Substance % w / w Occupation Dextrocetamine hydrochloride 1 Ingredient Active Clonidine hydrochloride 0.03 Ingredient Active Carboxypolymethylene * 1.5 Gel matrix Cetostearyl alcohol** 3.5 Emulsifier Mineral oil*** 2.0 Lipophilic phase Capric acid triglycerides caprylic 2.5 Lipophilic phase Propylene glycol **** 5.0 Humectant Parabens and phenoxyethanol 0.5 Preservative Disodium edetate dihydrate 0.05 Chelating Triethanolamine q.s.p. pH 4-7 Neutralizing Water for injections q.s.p 100 Diluent

* Carbopol 980NF ** Ethoxylated ceto-stearyl alcohol 20 *** Density 0.875g / mL **** Density 1.036g / mL [088] The process for preparing the composition described in Table 1 follows the steps described below:

A - Add the emulsifier, the lipophilic phase, the humectant and the preservative to a homogenizer; keep the mixture at a maximum temperature of 80 ° C and mix;

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B - Add purified water, mix and start cooling the mixture until a temperature between 60 ° C and 70 ° C is obtained;

C - Add the polymeric gel matrix and mix, keeping the mixture at a temperature between 60 ° C and 70 ° C;

D - Cool the mixture to a maximum temperature of 40 ° C;

E - Solubilize dextrocetamine hydrochloride, clonidine hydrochloride and the chelating agent in purified water and add the resulting solution to the homogenizer;

F - Add the neutralizing agent to adjust the pH in the range between 4 and 7 and homogenize;

G - Adjust the final weight with purified water and mix;

H - Deaerate and fill.

[089] Lots of the topical composition described above were manufactured to carry out Phase I (Example 3) and Phase II / III (Example 5) Clinical Studies. All lots were subjected to Accelerated Stability Studies (40 ° C ± 2 ° C and 75% ± 5% RH) and Long Term (30 ° C ± 2 ° C and 75% ± 5% RH), in addition to analyzes microbiological and physical-chemical. The results confirm the stability of the composition of the present invention and support a shelf life of 24 months (storage at room temperature, between 15 to 30 ° C, protected from light and moisture).

[090] The topical composition that exemplifies the present invention has an excellent spread on the skin, providing comfort to the patient at the time of application, especially in the case of patients with neuropathic pain.

Example 2 - Cutaneous Permeation Test of Clonidine Hydrochloride and Dextrocetamine Hydrochloride in a vertical diffusion cell determined by LC-MS / MS.

[091] An in vitro assay to assess skin permeation of the composition of the present invention described in Example 1 was carried out in accordance with OECD 428 (“Skin Absorption: in

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27/33 next, in vitro skin invention Method ”), using a vertical diffusion cell with determination of the active contents by LC-MS / MS.

[092] The composition of the present invention as described by Example 1 showed a cutaneous permeation of dextrocetamine hydrochloride of 268.69 ± 146.12 gg.cm ^- after 24 hours of study and permeation rate in relation to the time of 12.76 ±

6.7 6 gg.cm ^- .h ^- . The rate of skin permeation for

1 clomdma hydrochloride was 0.16 ± 0.11 gg.cm ^- .h ^- , ₂ totaling 3.56 ± 2.05 gg.cm ^- after 24 hours.

[093] Cutaneous permeation rates of ketamine and clonidine equivalent to those observed in the present invention are not obtained by compositions described in the State of the Art further proving one of the surprising effects of Just to exemplify, the rate of permeation of ketamine in relation to

12.7 6 ± 6.7 6 gg.cm ^-2 .h ^-1 is approximately 3 times higher than the permeation of this drug as described by the document at the time of

US6638981.

Example 3 - Pharmacokinetics: Systemic availability of ketamine and clonidine after topical administration in a single dose in healthy male volunteers of topical composition of the present invention (Phase I clinical study).

[094] Two grams of the topical pharmaceutical composition of the present invention as shown in Example ₂ were first applied in an area of 100 cm ^2, delimited in the belly of the volunteers, who were observed for 72 hours. Serial samples (10 mL of blood) were collected (baseline, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 9h, 12h, 24h and 48h) of blood to assess the systemic availability of the product components . The gel emulsion was rubbed with the gloved hand until completely absorbed. Twelve male individuals were selected. No adverse events were recorded.

[095] The collected samples were analyzed after liquid / liquid extraction using high performance liquid chromatography.

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28/33 efficiency with mass spectrophotometer detection (LC / MSMS).

[096] The results of the pharmacokinetic parameters of dextrocetamine are described in table 2 and Figure 1. Table 2. Dose and pharmacokinetic parameters for dextrocetamine determined in the Phase 1 Study.

Subject Dose pg / kg Cmax ng.mL ^- T ^T max ¹ h AUC (0-t) ng-h.mL ¹ AUC (0 _- «) ng-h.mL ^-1 001 394.5 2.4, 9.0 54.1 55.8 002 324.7 0.7 12.0 19.5 24.0 003 347.8 2.0 6.0 38.3 41.4 004 260.1 1.8 12.0 65.7 66.5 005 298.5 2.3 6.0 20.4 23.8 006 254.1 1.2 9.0 30.4 33.5 007 261.1 1.0 12.0 11.8 12.0 008 336.7 1.6 12.0 20.1 21.9 009 327.3 1.3 9.0 16.8 23.3 010 310.6 1.0 9.0 12.0 13.7 011 286.5 1.0 9.0 18.4 33.8 012 333.9 1.6 9.0 41.0 41.8 Average 311.3 1.5 9.5 29.0 32.6 SD 41.6 0.6 2.2 17.3 16.5 CV 13.4% 36.0% 22.7% 59.6% 50.5% SE 12.0 0.2 0.6 5.0 4.8 Minimum 254.1 0.7 6.0 11.8 12.0 median 317.7 1.5 9.0 20.3 28.8 maximum 394.5 2.4 12.0 65.7 66.5 [097] A application topical 2 g of composition topical gift invention results low bioavailability systemic dextrocetamine, which presented a Cmax fence 90 times smaller and an AUC about 8 times less than infusion 0.33 mg.mL IV ¹ ketamine (10 mg. kg!), dose bottom to that used in anesthesia. Were not reported

adverse events related to the drug, concluding that its plasma concentration was low enough to guarantee the absence of the commonly observed systemic physiological changes observed.

[098] Topical application of 2 g of the topical composition of the present invention did not result in a plasma clonidine concentration greater than 50 pg / mL (limit of detection of the method used) and in case the clonidine was eventually

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29/33 absorbed despite not being detected, its plasma concentration was not sufficient to cause changes in the blood pressure of the volunteers.

[099] Thus, the topical composition of the present invention, despite having a skin permeability coefficient higher than the topical compositions described in the nearest State of the Art, does not provide drugs systemically in concentrations capable of causing the widely known adverse / side effects by a technician on the subject. It is concluded that the topical composition of the present invention is safe, allowing the localized absorption of drugs and guaranteeing their locally restricted pharmacological action.

Example 4 - Acute and subacute toxic effects on human skin after application of the topical composition of the present invention.

A - Primary and Accumulated Dermal Irritation, and Dermal Sensitization.

[100] Monocentric study where the topical composition was evaluated on the skin of 52 healthy volunteers for 6 weeks.

[101] Primary dermal irritation was assessed by applying semi-occlusive dressings containing the topical composition of the present invention or the control of saline solution on the volar surface of the volunteers' forearms, 1 cm ² , 1 cm apart. The evaluations were performed after 48 and 96 hours of application according to the reading scale recommended by the International Contact Dermatitis Research Group (ICDRG).

[102] Semi-occlusive dressings as described above were applied to assess accumulated skin irritation. The readings according to the reading scale recommended by the International Contact Dermatitis Research Group (ICDRG) were performed every 48 hours for 3 weeks, thus completing 9 evaluations. After each assessment,

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30/33 dressings were reapplied in the same site, totaling 9 applications of the evaluated compositions.

[103] After the last application to assess accumulated skin irritation, the volunteers were on break for a period of 2 weeks and returned to the sensitization phase (challenge). Then, semi-occlusive dressings were applied, as previously described, in a virgin area. The readings (ICDRG) were taken every 48 and 72 hours after application of the dressings.

[104] No potential for Primary, Accumulated Dermal Irritation and Dermal Sensitization was observed after applying the topical composition of the present invention.

B - Photoirritation and dermal photosensitization.

[105] A monocentric study was carried out to determine the dermal photoirritation (FI) and dermal photosensitization (photoallergy) (FS) of the topical composition of the present invention, where the topical composition was evaluated on the skin of the back and forearms of 25 volunteers for 05 weeks . The volunteers were subjected to scarification of the corneal layer through the use of cellophane tape on the volar surface of the forearm for 5 times, followed by the application of semi-occlusive dressings of 1 cm ² , 1 cm apart, containing the topical composition of the present invention or saline control. After 02 hours the semi-occlusive dressing was removed and the region was irradiated with UVA at a dose of _ 2

J.cm. The evaluations were carried out after 24 hours according to the reading scale recommended by the International Contact Dermatitis Research Group (ICDRG).

[106] Semi-occlusive dressings as described above were applied to assess the

Dermal photosensitization (photoallergy). In this case, after hours the semi-occlusive dressings were removed and the _2 region was irradiated with UVA at a dose of 4 J.cm ^_2 . New irradiations and applications were carried out every 24 or 48 hours, for a period of 2 weeks, making a total

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31/33 of 6 irradiations. After the last application described, the volunteers were on break for a period of 02 weeks and returned to the challenge phase. Then, 2 groups of dressings were applied, as previously described, in a virgin area. After 24 hours the semi-occlusive dressing was removed and only one of the regions was irradiated with UVA at a dose of 4 J.cm. In both areas (irradiated and non-irradiated), readings (ICDRG) were taken 48 hours after irradiation. The evaluations were carried out after 24 hours according to the reading scale recommended by the International Contact Dermatitis Research Group (ICDRG).

[107] No photoirritation and photosensitization potential was observed after application of the topical composition of the present invention.

[108] Thus, it is concluded that the acute and subacute toxic effects on human skin exposed or not to UV radiation have shown that the topical composition of the present invention is safe for continuous use. No volunteer had a skin reaction related to the medication.

Example 5 - Multicenter, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of the composition of the present invention in the treatment of neuropathic pain syndromes (of diabetic, herpetic or leprosy origin).

[109] The analgesic efficacy of the topical composition of the present invention (Example 1) was compared to the isolated components (emulsion-gel of dextrocetamine hydrochloride 1% and clonidine hydrochloride 0.03%) and placebo (emulsion-gel), in 32 patients (Figure 2) for the treatment of neuropathic pain syndromes associated with: Peripheral Diabetic Neuropathy (NDP), post-herpetic neuralgia (NPH), postoperative or post-traumatic peripheral neuropathy and leprosy.

[110] Table 3 below provides a description of the patients recruited to participate in the study, who received 2

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32/33 g of the evaluated compositions, twice a day, for 12 weeks.

Table 3. Characteristics of patients recruited to participate in the phase II / III clinical study.

Arm Genre Age - years Weight - kg Height (cm) BMI (kg.m ^-2 ) F M med min max mean ± SD mean ± SD mean ± SD A. Dextrocetamine + Clonidine 6 3 47 22 71 67.2 ± 13 162.0 ± 9 25.7 ± 4.5 B. Dextrocetamine 3 7 55 29 74 68.0 ± 10.6 163.0 ± 11 25.8 ± 2.8 C. Clonidine 8 1 63 31 79 65.3 ± 16.2 159.0 ± 13 25.6 ± 3.4 D. Placebo 6 4 53 35 61 67.6 ± 12.1 158.0 ± 9 27.3 ± 4.9

[111] Pain intensity was assessed every 24 hours by the patient in the morning, before applying the investigational product, selecting the number of the 11-point numerical pain rating scale that best describes their pain in the period (NRS-PI; 0 = “no pain” and 10 = “worst possible pain”, Visual Analogue Scale). The mean weekly pain score was calculated for each patient and used to assess the change in mean pain intensity from baseline (dorbasal = 4 assessments in the last 7 days preceding Visit 2) to week 12 (dorsem12 = final score ).

[112] Figure 3 demonstrates a significant reduction in pain intensity for groups A, B and C compared to placebo (Group D), clearly indicating the superiority of the composition of the present invention containing the association of assets over compositions containing active alone, especially from 5 ^to week of treatment.

[113] It is observed that the application of the isolated drugs reduced pain until the fourth week of treatment, when the mean remained stable. On the other hand, and surprisingly, the combination of the two drugs showed continuous benefit throughout the treatment. The placebo group showed no significant change in mean pain over 12 weeks even

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33/33 without interrupting the treatment previously prescribed at the beginning of the study.

[114] In addition, as illustrated in Figure 4, in the group treated with the combination ketamine + clonidine (Group A), all patients experienced pain relief, especially those suffering from moderate and severe pain, while for Groups B and C, at the end of 12 weeks there were still patients in the severe pain category.

[115] The analysis of the results shows the therapeutic efficacy of the topical composition of the present invention, in particular of the topical composition comprising the association between dextrocetamine hydrochloride 1% and clonidine hydrochloride 0.03%, in the treatment of neuropathic pain, in relation to placebo.

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1/4

Claims (23)

1. Topical pharmaceutical composition characterized by comprising ketamine or a pharmaceutically acceptable salt thereof in the concentration of 0.5% to 5% w / w and clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.01% to 0.1% w / w . Topical pharmaceutical composition according to claim 1, characterized in that it comprises ketamine or a pharmaceutically acceptable salt thereof in the concentration of 1% to 2% w / w and clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.03% to 0.06 % w / w. Topical composition according to claim 1 or 2, characterized in that ketamine and clonidine, or a pharmaceutically acceptable salt thereof, are present in the proportion of 1: 0.03. Topical pharmaceutical composition according to claims 1, 2 or 3, characterized in that it comprises ketamine or a pharmaceutically acceptable salt thereof in the concentration of 1% w / w and clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.03% w / w . Topical pharmaceutical composition according to claims 1, 2, 3 or 4, characterized in that ketamine is dextrocetamine hydrochloride and clonidine is clonidine hydrochloride. Topical pharmaceutical composition according to claim 1, characterized in that it is in the form of an emulsion. Topical pharmaceutical composition according to claim 1 or 6, characterized in that it is in the form of emulsion-gel. 8. Topical pharmaceutical composition characterized by Petition 870160078604, of 12/22/2016, p. 14/51 2/4 be an emulsion-gel comprising ketamine or a pharmaceutically acceptable salt thereof, clonidine or a pharmaceutically acceptable salt thereof, or combinations thereof. Topical pharmaceutical composition according to claim 8, characterized in that it comprises ketamine or a pharmaceutically acceptable salt thereof in the concentration of 0.5% to 5% w / w, clonidine or a pharmaceutically acceptable salt thereof in the concentration of 0.01 to 0 , 1% w / w, or combinations thereof. Topical pharmaceutical composition according to claim 8 or 9, characterized in that ketamine and clonidine, or a pharmaceutically acceptable salt thereof, are present in the proportion of 1: 0.03. Topical pharmaceutical composition according to claims 8, 9 or 10, characterized in that ketamine is dextrocetamine hydrochloride and clonidine is clonidine hydrochloride. Topical pharmaceutical composition according to claims 8, 9, 10 or 11, characterized in that it is a water / oil emulsion gel and comprises: a) a polymeric gel matrix; b) a fatty alcohol emulsifier; c) a lipophilic phase, d) a humectant; e) a preservative, f) a chelating agent, g) a neutralizing agent for pH adjustment between 4 and 7 and h) purified water. Topical pharmaceutical composition according to claim 12, characterized in that a) it is carboxypolymethylene and b) it is ceto-stearyl alcohol. Topical pharmaceutical composition according to claim 13, characterized in that it comprises: a) carboxypolymethylene; b) ceto-stearyl alcohol; c) mineral oil and capric and caprylic acid triglycerides, d) propylene glycol; e) parabens and phenoxyethanol; f) edetate Petition 870160078604, of 12/22/2016, p. 15/51 3/4 disodium; g) a neutralizing agent to adjust the pH between 4 and 7 and h) purified water. Topical pharmaceutical composition according to claim 12, characterized in that it comprises: a) a polymeric gel matrix in the concentration of 0.5% to 3% w / w; b) a fatty alcohol emulsifier in a concentration of 2% to 5% w / w; c) a lipophilic phase at a concentration of 1.5% to 15% w / w; d) a humectant in the concentration of 3% to 15% w / w; e) a preservative in the concentration of 0.01% to 2% w / w; f) a chelating agent at a concentration of 0.005% to 0.1% w / w; g) a neutralizing agent to adjust the pH between 4 and 7 and h) purified water. Topical pharmaceutical composition according to claim 14, characterized in that it comprises: a) carboxypolymethylene in a concentration of 1.5% w / w; b) ceto-stearyl alcohol at a concentration of 3.5% w / w; c) mineral oil and caprylic caprylic acid triglycerides at a concentration of 4.5% w / w; d) propylene glycol at a concentration of 5% w / w; e) parabens and phenoxyethanol at a concentration of 0.5% w / w; f) disodium edetate at a concentration of 0.05% w / w; g) a neutralizing agent to adjust the pH between 4 and 7 and h) purified water. 17. Topical pharmaceutical composition according to claim 1 or 8, characterized in that it is useful in the prevention and treatment of disorders or conditions in which pain predominates, including acute and chronic pain. 18. Topical pharmaceutical composition according to claim 1 or 8, characterized by the fact that it is useful in the prevention and treatment of neuropathic pain syndromes. 19. Topical pharmaceutical composition according to claim 1 or 8, characterized in that it is useful in the prevention and treatment of neuropathic pain syndromes Petition 870160078604, of 12/22/2016, p. 16/51 4/4 associated with peripheral diabetic neuropathy; postherpetic neuralgia; postoperative peripheral neuropathy or post-traumatic peripheral neuropathy and leprosy. 20. Use of topical pharmaceutical composition as defined in claim 1 or 8, characterized by the fact that it is in the manufacture of a medication for the prevention and treatment of disorders or conditions in which pain predominates, including acute and chronic pain. 21. Use of topical pharmaceutical composition as defined in claim 1 or 8, characterized by the fact that it is in the manufacture of a medication for the prevention and treatment of neuropathic pain syndromes. 22. Use of topical pharmaceutical composition as defined in claim 1 or 8, characterized by the fact that it is in the manufacture of a medication for the prevention and treatment of neuropathic pain syndromes associated with peripheral diabetic neuropathy; post-herpetic neuralgia; postoperative peripheral neuropathy or post-traumatic peripheral neuropathy and leprosy. acute and administration to a treatment of a 23. Method of prevention and treatment of disorders or conditions in which pain predominates, including chronic pain, characterized by understanding the need for the effective dose of the individual in a therapeutically dose topical pharmaceutical composition according to claim 1 or 8. Petition 870160078604, of 12/22/2016, p. 17/51 1/4