WO2012139191A1 - Pharmaceutical compositions containing 11,12-pyrazole minocycline and use thereof for relieving pain of neuropathic origin - Google Patents

Pharmaceutical compositions containing 11,12-pyrazole minocycline and use thereof for relieving pain of neuropathic origin Download PDF

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WO2012139191A1
WO2012139191A1 PCT/BR2012/000112 BR2012000112W WO2012139191A1 WO 2012139191 A1 WO2012139191 A1 WO 2012139191A1 BR 2012000112 W BR2012000112 W BR 2012000112W WO 2012139191 A1 WO2012139191 A1 WO 2012139191A1
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pharmaceutical compositions
neuropathic pain
minocycline
pain relief
drugs
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PCT/BR2012/000112
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French (fr)
Portuguese (pt)
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Leandro Francisco SILVA BASTOS
Jeferson GOMES DA SILVA
Márcio DE MATOS COELHO
Heloisa De Oliveira Beraldo
Márcio Flávio DUTRA MORAES
Daniel DE ASSIS SANTOS
Simone GONÇALVES DOS SANTOS
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Universidade Federal De Minas Gerais - Ufmg
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/65Tetracyclines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention describes pharmaceutical compositions containing the 1,112-pyrazolaminocycline hydrochloride compound (HPMCCI) - a minocycline derivative (HMCCI) - and pharmaceutically acceptable excipients, and their use for relieving neuropathic pain.
  • HPMCCI-containing composition may be used alone or in combination with other drugs to treat patients with neuropathic pain.
  • the compound HPMCCI has no antimicrobial effect, which, compared to minocycline, can reduce adverse reactions, allowing greater adherence of patients to treatment.
  • Tetracyclines were discovered in the late 1940s and are a family of natural drugs derived from the metabolites of different Streptomyces sp. (chlortetracycline, oxytetracycline) as well as semi-synthetic drugs (metacycline, doxycycline, HMCCI, limecycline, rolitetracycline and tigecycline). Chlortetracycline and oxytetracycline are drugs obtained from Streptomyces aureofaciens and Streptomyces rimosus, respectively.
  • tetracyclines were later discovered, including Streptomyces aureofaciens tetracycline, Streptomyces rimosus and Streptomyces viridofaciens and Streptomyces demethylchloretracycline. aureofaciens.
  • the most recently discovered member of this pharmacological class was tigecycline, a third generation tetracycline derived from HMCCI that has been approved in the United States of America for the treatment of patients with severe skin and intra-abdominal infections (CHOPRA, I .; ROBERTS , M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance (Microbiol Mol Biol Rev, v. 65, no. 2, pp. 232-60, 2001).
  • Tetracyclines inhibit bacterial protein synthesis by preventing coupling of the transporter aminoacyl RNA to the ribosomal receptor site. They are drugs that induce a predominantly bacteriostatic effect, showing activity against several Gram-positive and Gram-positive bacteria. negative and also against chlamydia, mycoplasma, rickettsia and protozoa. In addition, some tetracycline derivatives are potent antifungal agents. Doxycycline has been included in the model list of essential drugs proposed by the World Health Organization (WHO, 2010) not only in the class of antibacterial drugs, but also in the class of drugs used for malaria prophylaxis and treatment of patients with this parasitic disease.
  • WHO World Health Organization
  • Doxycycline and HMCCI second generation tetracyclines
  • CMT-3 A chemically modified tetracycline (CMT-3) is a new antifungal agent.
  • PEREZ-TRALLERO E.; IGLESIAS, L. Tetracyclines, sulfonamides and metronidazole., Nurse Infecc Microbiol Clin, v. 21, no. 520-8, 2003. World Health Organization (WHO), 2010. Essential Drug Lists ⁇ http://www.who.int/medicines/publications/essentialmedicines/en/index.html> Accessed 10/27/201 1 ).
  • HMCCI tetracycline whose non-antimicrobial activities are most widely studied. These activities include anti-inflammatory, neuroprotective and antinociceptive activities.
  • RAGHAVENDRA nociceptive, inflammatory and neuropathic pain
  • HMCCI in the treatment of patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, traumatic brain injury, Huntington and Parkinson (www.clinicaltrials.com. Accessed on 10/1 1/201 1).
  • LA RANA G. et al. AM404, anandamide transport inhibitor, plasma plasma extravasation in a model of neuropathic pain in rat: role for cannabinoid receptors Neuropharmacology, v. 54, no. 3, pp. 521-9, 2008.
  • Drugs such as acetylsalicylic acid, ibuprofen and paracetamol are on the WHO list of essential drugs in the non-steroidal anti-inflammatory class, and morphine and codeine have been included in the opioid analgesic class (WHO, 2010).
  • WHO opioid analgesic class
  • these drugs have very limited utility in treating patients with painful conditions associated with neuropathies, conditions that represent a serious public health problem worldwide, and have a prevalence of between 7 and 8% in developed countries, where epidemiological studies have already been conducted. .
  • gabapentin and pregabalin, anticonvulsant drugs they have been approved in some countries for the treatment of patients with neuropathic pain. (TORRANCE, N. et al.
  • Patent application WO9626926 describes the synthesis of 1,112-pyrazoltetracyclines derivatives and their use as antibiotics, but there are no reports of their use for pain management.
  • HPMCCI-induced antinociceptive effect in neuropathic pain models.
  • the use of HPMCCI in the treatment of neuropathic pain is associated with several advantages, since the few drugs available to treat patients with diseases of this nature are not very effective, associated with the fact that HPMCCI is potentially safer than HMCCI as it is devoid of antimicrobial activity.
  • FIG. 1 Chemical structure of 1,112-pyrazolminocycline hydrochloride (HPMCCI).
  • FIG. 3 Electronic spectra of minocycline hydrochloride (HMCCI) in TRIS 7.2 buffer after successive additions of CaCl3 in TRIS 7.2 buffer.
  • HMCCI minocycline hydrochloride
  • FIG. 4 HPMCCI electronic spectra in TRIS 7.2 buffer after successive additions of CaCl 2 .
  • Figure 5 HPMCCI-induced antinociceptive effect at doses of 50 and 100 mg / kg in the mechanical allodynia model developed 10 days after sciatic nerve constriction in rats. Baseline paw withdrawal thresholds were determined prior to surgery or treatment. On the tenth day after surgery, the thresholds were determined again before the treatments.
  • the present invention comprises pharmaceutical compositions containing the 1,2-pyrazolminocycline hydrochloride compound (HPMCCI) - a minocycline derivative (HMCCI) - and pharmaceutically acceptable excipients, and their use for the relief of neuropathic pain.
  • HPMCCI 1,2-pyrazolminocycline hydrochloride compound
  • HMCCI minocycline derivative
  • compositions may be presented in solid forms such as tablets, pills, capsules and suppository; liquid, such as solutions, suspensions and syrups; as well as aerosols, pastes, creams, ointments and lotions for local application or as transdermal devices. Its administration can be by oral, rectal, intravenous, intrathecal, epidural or topical routes.
  • HPMCCI can be used alone or in combination with other drugs commonly used to treat patients with neuropathic pain, such as opioids (morphine, codeine, oxycodone, hydrocodone, tramadol), non-steroidal anti-inflammatory drugs (diclofenac sodium or potassium).
  • opioids morphine, codeine, oxycodone, hydrocodone, tramadol
  • non-steroidal anti-inflammatory drugs diclofenac sodium or potassium
  • acetylsalicylic acid paracetamol, ibuprofen, cetroprofen, naproxen, flurbiprofen
  • pain relieving anticonvulsants carbamazepine, oxcarbazepine, gabapentin, pregabalin
  • pain relieving antidepressants amitriptyline, nortriptyline, fluoxetine
  • rheumatoid arthritis etanercept, infliximab, adalimumab, certolizumab, golimumab, anakinra, rituximab, abatacept, tocilizumab
  • medicines used for prophylaxis of migraine propranolol, atenolol, metoprolol.
  • the present invention has the absence of antibacterial and antifungal activity, possibly decreasing side effects compared to HMCCI.
  • Example 2 Evaluation of the interaction of HMCCI and HPMCCI compounds with calcium (11) The ability of the HMCCI and HPMCCI compounds to interact with calcium (11) was assessed by spectrophotometric titration involving 3 ml of an aqueous solution of the compound at pH 7. 2 (maintained by the TRIS buffer solution) with aliquots of calcium chloride solution (ll). The system was kept at 25 ° C. Figures 3 and 4 show the electronic spectra obtained during the experiment.
  • the first antibacterial activity tests were performed quantitatively by the serial macrodilution method. Antibacterial activity tests were performed following NCCLS standards (2002, 2003). Staphylococus aureus (ATCC ® 6538) and Pseudomonas aeruginosa (ATCC ® 27853) strains were inoculated into Mueller Hinton broth, both incubated at 37 ° C for 18 to 24 h (PERNAK, J. et al. Synthesis and antimicrobial activities of new pyridinium and benzimidazolum chlorides Eur J Med Chem, v. 36, no. 4, pp. 313-20, 2001).
  • the reference for inoculum turbidity was measured by analyzing its absorption spectrum in the visible region at wavelengths 530 nm and 625 nm and should provide an absorbance value between 0.08 and 0.1, so that the The inoculum concentration is 10 8 colony forming units (CFU). 100 ⁇ _ were taken from the inoculum and transferred to another tube containing 9.9 ml_ Mueller Hinton broth, so that the inoculum concentration in this tube was 10 6 CFU.
  • HMCCI was used as a positive control in tests designed to evaluate the activity of its derivative against S. aureus and P. aeruginosa. After 20 h incubation at 37 ° C, the minimum inhibitory concentrations (MIC) of the compounds were determined.
  • Table 2 MIC values found for HMCCI against S. aureus ATCC '6538 and P. aeruginosa ATCC® 9027
  • the MIC values are in accordance with the range of values presented for this compound against quality control strains.
  • the increase in HPMCCI MIC values, when compared with those of the starting tetracycline, may be attributed to the pyrazole ring formation with the presence of carbon-bound nitrogen C 1 1 and C12, which led to the loss of antibacterial activity (SAIKALI, Z .; SINGH, G. Doxycycline and other tetracyclines in the treatment of bone metastasis (Anticancer Drugs, v. 14, no. 10, pp. 773-8, 2003).
  • a second battery of tests was performed using ninety clinical samples: 30 Staphylococcus aureus, 30 Staphylococcus spp. negative coagulase and 30 of Escherichia coli.
  • the strains were sensitive to a wide range of antibacterial drugs, as demonstrated in a test conducted according to the method proposed by the Clinical Laboratories Standards Institute (CLSI, 2011).
  • MIC minimal inhibitory concentrations of minocycline and HPMCCI were assessed by the agar dilution method (CLSI, 201 1). Drug stock solutions were added to Muller-Hinton agar (BD Difco TM, USA) leading to final concentrations of 0.125 to 64 pg / mL. Bacterial inocula were prepared by direct suspension of the colony in saline to obtain a density equivalent to the 0.5 McFarland standard (approximately 1 x 10 8 colony-forming units / mL) and then inoculated onto the Muller-Hinton agar with the drugs using a replicator. Steers (Steers, Foltz et al., 1959).
  • Staphylococcus aureus (ATCC® 25923) reference strains Staphylococcus epidermidis (ATCC® 12228) and Escherichia coli (ATCC® 25922) were included as a control.
  • the MIC was considered the lowest concentration sufficient to inhibit bacterial growth following CLSI standards (201 1).
  • HMCCI 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  • HMCCI 9 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  • the bacteria tested are considered sensitive to HMCCI when their growth inhibited at a concentration of 16 pg / mL or less, CLSI 201 1.
  • Example 4 Evaluation of HPMCCI Antifungal Activity Eleven Candida albicans strains were included in this study. All samples were kept on Sabouraud dextrose agar at 4 ° C. Prior to testing, samples were transferred to a new tube containing Sabouraud dextrose agar at 37 ° C for 24 h. Fungi suspensions were prepared in saline (0.85% sodium chloride, m / v) and the transmittance was adjusted to 85% at 530 nm on a spectrophotometer.
  • the resulting suspension (1 to 5 X 10 6 colony forming units / mL) was vortexed for 15 h and cell density was adjusted to 1 to 5 X 0 3 colony forming units / mL in RPMI-1640 medium (Inlab, Brazil).
  • the microdilution assay was conducted using sterile RPMI-1640 medium buffered with morpholinopropanesulfonic acid (0.155 mol / L, Sigma-Aldrich, USA) as the test medium.
  • the solutions containing each of the drugs tested were dissolved in distilled and sterile water. Then, serial dilution in RPMI-1640 was performed, finally obtaining a concentration range of 128 to 0.25 pg / mL.
  • Results were expressed in ng / mL, and MIC was visually defined as the lowest concentration capable of inhibiting fungal growth when compared to the control group.
  • MIC was capable of inhibiting 80% of fungal growth (NCCLS, 2002).
  • Surgical nerve constriction procedures are based on the technique described by Bennett and Xie, 1988 (BENNETT, GJ; XIE, YK. Peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, v. 33, n 1, pp. 87-107, 1988).
  • Figure 4 shows the threshold curves for right paw withdrawal as a function of time after intraperitoneal (i.p.) administration of the HPMCCI compound or its vehicle in rats undergoing sciatic nerve constriction surgery or false surgery.
  • Example 6 Antinociceptive effect of HPMCCI administered per os.
  • HPMCCI administered per os is of great importance in a therapeutic context, as oral administration is the most convenient for drug administration.
  • Figure 6 shows data on the antiallodynamic effect of per os administered HPMCCI, which can be achieved by increasing the intraperitoneally administered effective dose by 5-fold (from 50 to 250 mg / kg).
  • Surgery was performed as previously described in Example 5, and the drug was administered by gavage, in a volume of 2 mL / kg, in saline containing 5% sucrose m / v (Labsynth ® , Diadema, Brazil).

Abstract

The present invention describes pharmaceutical compositions containing the compound 11,12-pyrazole minocycline hydrochloride (HPMCCl) - a minocycline (HMCCl) derivative - and pharmaceutically acceptable excipients, and use thereof for relieving neuropathic pain. The composition containing HPMCCl may be used alone or in combination with other drugs for treating patients with neuropathic pain. The HPMCCl compound has no antimicrobial effects, which, in comparison to minocycline, may decrease the side effects, with a greater possibility of the patients adhering to the treatment.

Description

COMPOSIÇÕES FARMACÊUTICAS CONTENDO 11 ,12- PIRAZOLMINOCICLINA E USO PARA ALÍVIO DE DOR DE ORIGEM PHARMACEUTICAL COMPOSITIONS CONTAINING 11, 12- PYRAZOLMINOCYCLINE AND USE FOR PAIN RELIEF
NEUROPÁTICA NEUROPATHIC
A presente invenção descreve composições farmacêuticas contendo o composto cloridrato de 1 1 , 12-pirazolminociclina (HPMCCI) - um derivado da minociclina (HMCCI) - e excipientes farmaceuticamente aceitáveis, e seu uso para alívio de dor neuropática. A composição contendo HPMCCI pode ser utilizada isoladamente ou em associação com outros fármacos para o tratamento de pacientes portadores de dor neuropática. O composto HPMCCI não apresenta efeito antimicrobiano, o que, em comparação à minociclina, pode reduzir as reações adversas, possibilitando maior adesão dos pacientes ao tratamento.  The present invention describes pharmaceutical compositions containing the 1,112-pyrazolaminocycline hydrochloride compound (HPMCCI) - a minocycline derivative (HMCCI) - and pharmaceutically acceptable excipients, and their use for relieving neuropathic pain. The HPMCCI-containing composition may be used alone or in combination with other drugs to treat patients with neuropathic pain. The compound HPMCCI has no antimicrobial effect, which, compared to minocycline, can reduce adverse reactions, allowing greater adherence of patients to treatment.
As tetraciclinas foram descobertas ao final da década de 1940 e constituem uma família de fármacos naturais derivados dos metabólitos de diferentes espécies de Streptomyces sp. (clortetraciclina, oxitetraciclina), bem como de fármacos semissintéticos (metaciclina, doxiciclina, HMCCI, limeciclina, rolitetraciclina e tigeciclina). A clortetraciclina e a oxitetraciclina são fármacos obtidos de Streptomyces aureofaciens e de Streptomyces rimosus, respectivamente. Outras tetraciclinas foram descobertas posteriormente, entre as quais a tetraciclina de Streptomyces aureofaciens, Streptomyces rimosus e Streptomyces viridofaciens e a desmetilclortetraciclina de Streptomyces. aureofaciens. O membro dessa classe farmacológica descoberto mais recentemente foi a tigeciclina, uma tetraciclina de terceira geração derivada do HMCCI que foi aprovada nos Estados Unidos da América (EUA) para tratamento de pacientes com infecções cutâneas e intra-abdominais graves (CHOPRA, I.; ROBERTS, M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev, v. 65, n. 2, p. 232-60, 2001 ).  Tetracyclines were discovered in the late 1940s and are a family of natural drugs derived from the metabolites of different Streptomyces sp. (chlortetracycline, oxytetracycline) as well as semi-synthetic drugs (metacycline, doxycycline, HMCCI, limecycline, rolitetracycline and tigecycline). Chlortetracycline and oxytetracycline are drugs obtained from Streptomyces aureofaciens and Streptomyces rimosus, respectively. Other tetracyclines were later discovered, including Streptomyces aureofaciens tetracycline, Streptomyces rimosus and Streptomyces viridofaciens and Streptomyces demethylchloretracycline. aureofaciens. The most recently discovered member of this pharmacological class was tigecycline, a third generation tetracycline derived from HMCCI that has been approved in the United States of America for the treatment of patients with severe skin and intra-abdominal infections (CHOPRA, I .; ROBERTS , M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance (Microbiol Mol Biol Rev, v. 65, no. 2, pp. 232-60, 2001).
As tetraciclinas inibem a síntese proteica bacteriana ao impedir o acoplamento do aminoacil-RNA transportador ao sítio receptor ribossômico. São fármacos que induzem efeito predominantemente bacteriostático, apresentando atividade contra várias bactérias Gram-positivas e Gram- negativas e também contra clamídias, micoplasmas, riquétsias e protozoários. Além disso, alguns derivados de tetraciclina são potentes agentes antifúngicos. A doxiciclina foi incluída na lista modelo de medicamentos essenciais proposta pela Organização Mundial da Saúde (OMS, 2010) não somente na classe dos antibacterianos, mas também na classe dos medicamentos usados na profilaxia da malária e no tratamento de pacientes portadores dessa doença parasitária. A doxiciclina e o HMCCI, tetraciclinas de segunda geração, são as mais bem absorvidas (90-100%) após administração oral (LIU, Y. et al. A chemically modified tetracycline (CMT-3) is a new antifungal agent. Antimicrob Agents Chemother, v. 46, n. 5, p. 1447-1454, 2002. PEREZ-TRALLERO, E.; IGLESIAS, L. Tetracyclines, sulfonamides and metronidazole. Enferm Infecc Microbiol Clin, v. 21 , n. 9, p. 520-8, 2003. Organização Mundial da Saúde (OMS), 2010. Listas de Medicamentos Essenciais <http://www.who.int/medicines/publications/essentialmedicines/en/index.html> Acesso em 27/10/201 1 ). Tetracyclines inhibit bacterial protein synthesis by preventing coupling of the transporter aminoacyl RNA to the ribosomal receptor site. They are drugs that induce a predominantly bacteriostatic effect, showing activity against several Gram-positive and Gram-positive bacteria. negative and also against chlamydia, mycoplasma, rickettsia and protozoa. In addition, some tetracycline derivatives are potent antifungal agents. Doxycycline has been included in the model list of essential drugs proposed by the World Health Organization (WHO, 2010) not only in the class of antibacterial drugs, but also in the class of drugs used for malaria prophylaxis and treatment of patients with this parasitic disease. Doxycycline and HMCCI, second generation tetracyclines, are best absorbed (90-100%) after oral administration (LIU, Y. et al. A chemically modified tetracycline (CMT-3) is a new antifungal agent. Antimicrob Agents Chemother, v. 46, No. 5, pp. 1447-1454, 2002. PEREZ-TRALLERO, E.; IGLESIAS, L. Tetracyclines, sulfonamides and metronidazole., Nurse Infecc Microbiol Clin, v. 21, no. 520-8, 2003. World Health Organization (WHO), 2010. Essential Drug Lists <http://www.who.int/medicines/publications/essentialmedicines/en/index.html> Accessed 10/27/201 1 ).
O HMCCI, aprovado para uso desde a década de 1970, é a tetraciclina cujas atividades não antimicrobianas são mais amplamente estudadas. Entre essas atividades podem ser citadas as anti-inflamatórias, neuroprotetoras e antinociceptivas. Estudos publicados na última década têm relatado efeitos em modelos de dor nociceptiva, inflamatória e neuropática (RAGHAVENDRA, V. et al. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther, v. 306, n. 2, p. 624-30, 2003. LEDEBOER, A. et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain, v. 1 15, n. 1 -2, p. 71-83, 2005. BASTOS, L. F. S. et al. A novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice. Br J Pharmacol, v. 155, n. 5, p. 714- 21 , 2008).  HMCCI, approved for use since the 1970s, is tetracycline whose non-antimicrobial activities are most widely studied. These activities include anti-inflammatory, neuroprotective and antinociceptive activities. Studies published in the last decade have reported effects on models of nociceptive, inflammatory and neuropathic pain (RAGHAVENDRA, V. et al. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther, v. 306, No. 2, pp. 624-30, 2003. LEDEBOER, A. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.Pain, v. 15, No. 1 -2, p. 71-83, 2005. BASTOS, LFS et al .. The novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline inhibits nociception and edema in mice Br J Pharmacol, v 155, no 5, pp 714-21 , 2008).
Os efeitos em modelos experimentais de dor têm sido associados com inibição da ativação de células microgliais, sendo que o mecanismo de ativação glial é considerado um alvo potencial para o desenvolvimento de fármacos para o tratamento de pacientes com doenças neurodegenerativas e condições dolorosas crónicas (WATKINS, L. R.; MAIER, S. F. Glia: a novel drug discovery target for clinicai pain. Nat Rev Drug Discov, v. 2, n. 12, p. 973- 85, 2003. MILLIGAN, E. D.; WATKINS, L. R. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci, v. 10, n. 1 , p. 23-36, 2009). Effects on experimental models of pain have been associated with inhibition of microglial cell activation, and the mechanism of glial activation is considered a potential target for the development of drugs for the treatment of patients with neurodegenerative diseases. chronic painful conditions (WATKINS, LR; MAIER, SF Glia: A Novel Drug Discovery Target for Clinical Pain. Nat Rev Drug Discov, v. 2, no. 12, p. 973-85, 2003. MILLIGAN, ED; WATKINS, LR Pathological and protective roles of glia in chronic pain Nat Rev Neurosci, v. 10, no. 1, pp. 23-36, 2009).
De fato, estudos clínicos têm sido conduzidos para testar a utilidade do In fact, clinical studies have been conducted to test the usefulness of
HMCCI no tratamento de pacientes com esclerose múltipla, esclerose lateral amiotrófica, acidente vascular encefálico, lesão cerebral traumática, Huntington e Parkinson (www.clinicaltrials.com. Acesso em 10/1 1/201 1 ). HMCCI in the treatment of patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, traumatic brain injury, Huntington and Parkinson (www.clinicaltrials.com. Accessed on 10/1 1/201 1).
Entretanto, uma limitação à sua possível utilidade no tratamento de pacientes com condições dolorosas crónicas consiste no seu efeito antimicrobiano. Devido a esse efeito, o seu uso prolongado pode gerar candidíase e distúrbios gastrintestinais, o que pode reduzir a adesão dos pacientes ao tratamento (GOULDEN, V. et al. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol, v. 134, n. 4, p. 693-5, 1996).  However, a limitation on its possible utility in treating patients with chronic painful conditions is its antimicrobial effect. Due to this effect, its prolonged use can generate candidiasis and gastrointestinal disturbances, which may reduce patients' adherence to treatment (GOULDEN, V. et al. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol, v. 134, no. 4, pp. 693-5, 1996).
Além dessas possíveis reações adversas, existem aquelas resultantes da quelação de cálcio. O HMCCI é contraindicado a gestantes, lactantes e crianças com idade inferior a oito anos por causa da possibilidade de formação de complexo com cálcio, com consequente deposição do composto em ossos. Outra possível consequência da quelação de cálcio é a ocorrência de manchas nos dentes (SANCHEZ, A. R. et al. Tetracycline and other tetracycline- derivative staining of the teeth and oral cavity. Int J Dermatol, v. 43, n. 10, p. 709-15,2004).  In addition to these possible adverse reactions, there are those resulting from calcium chelation. HMCCI is contraindicated in pregnant women, nursing mothers and children under the age of eight because of the possibility of calcium complex formation, with consequent deposition of the compound in bones. Another possible consequence of calcium chelation is the occurrence of tooth stains (SANCHEZ, AR et al. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol, v. 43, n. 10, p. 709 -15,2004).
Por essas razões, as chamadas tetraciclinas quimicamente modificadas têm sido desenvolvidas. Estudos clínicos têm sido conduzidos para testar a utilidade da inciclinida - uma tetraciclina quimicamente modificada -, no tratamento de pacientes com certos tipos de câncer (www.clinicaltrials.com. Acesso em 13/1 1/201 1 ). Derivados não antibacterianos do HMCCI também têm sido investigados (LERTVORACHON, J. et al. 1 , 12-substituted tetracyclines as antioxidant agents. Bioorg Med Chem, v. 13, n. 15, p. 4627-37, 2005). Apesar de existirem várias classes de fármacos úteis no tratamento de pacientes com condições dolorosas, existe uma grande demanda pela busca de fármacos com eficácia ou segurança superiores às dos atualmente disponíveis para uso clínico. Nesse sentido, existe grande interesse pela buscaFor these reasons, so-called chemically modified tetracyclines have been developed. Clinical studies have been conducted to test the usefulness of inciclinide - a chemically modified tetracycline - in treating patients with certain cancers (www.clinicaltrials.com. Accessed 1/13 1/201 1). Non-antibacterial derivatives of HMCCI have also been investigated (LERTVORACHON, J. et al. 1,12-substituted tetracyclines as antioxidant agents. Bioorg Med Chem, v. 13, no. 15, p. 4627-37, 2005). Although there are several classes of drugs useful in treating patients with painful conditions, there is a great demand for drugs with efficacy or safety superior to those currently available for clinical use. In this sense, there is great interest in the search
5 de drogas com atividade analgésica que interfiram na transmissão canabinoidérgica e bloqueadores de canais para sódio resistentes à tetrodotoxina (LA RANA, G. et al. AM404, an anandamide transport inhibitor, reduces plasma extravasation ín a model of neuropathic pain in rat: role for cannabinoid receptors. Neuropharmacology, v. 54, n. 3, p. 521 -9, 2008.5 of drugs with analgesic activity interfering with cannabinoid transmission and tetrodotoxin resistant sodium channel blockers (LA RANA, G. et al. AM404, anandamide transport inhibitor, plasma plasma extravasation in a model of neuropathic pain in rat: role for cannabinoid receptors Neuropharmacology, v. 54, no. 3, pp. 521-9, 2008.
I O SCANIO, M. J. et al. Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Na(v)1 .8 sodium channel with efficacy in a model of neuropathic pain. Bioorg Med Chem, v. 18, n. 22, p. 7816-25, 2010). SCANIO, M.J. et al. Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Na (v) 1.8 sodium channel with efficacy in a model of neuropathic pain. Bioorg Med Chem, v. 18, no. 22, p. 7816-25, 2010).
Além da busca por novos fármacos, têm sido demonstrados novos usos 15 para fármacos já disponíveis para uso clínico, tais como os agonistas de 2- adrenoceptores, os antagonistas de β-adrenoceptores, os anticonvulsivantes e os antidepressivos, que são atualmente alternativas terapêuticas menos convencionais.  In addition to the search for new drugs, new uses have been demonstrated 15 for drugs already available for clinical use, such as 2-adrenoceptor agonists, β-adrenoceptor antagonists, anticonvulsants and antidepressants, which are currently less conventional therapeutic alternatives. .
Fármacos como o ácido acetilsalicílico, ibuprofeno e paracetamol estão 0 presentes na lista de medicamentos essenciais proposta pela OMS na classe de medicamentos anti-inflamatórios não esteroides, e morfina e codeína foram incluídos na classe de analgésicos opioides (OMS, 2010). Entretanto, esses fármacos têm utilidade muito limitada no tratamento de pacientes com condições dolorosas associadas com neuropatias, condições que representam 15 um grave problema de saúde pública mundialmente, e têm uma prevalência entre 7 e 8% em países desenvolvidos, onde estudos epidemiológicos já foram conduzidos. Ao invés desses fármacos tradicionais, gabapentina e pregabalina, fármacos anticonvulsivantes, foram aprovados em alguns países para o tratamento de pacientes com dor neuropática (TORRANCE, N. et al. 30 The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain, v. 7, n. 4, p. 281 -9, 2006. BOUHASSIRA, D. et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain, v. 136, n. 3, p. 380-7, 2008. DRAY, A. Neuropathic pain: emerging treatments. Br J Anaesth, v. 101 , n. 1 , p. 48-58, 2008. Organização Mundial da Saúde (OMS), 2010. Listas de Medicamentos Essenciais <http://www.who.int/medicines/publications/ essentialmedicines/en/index.html> Acesso em 27/ 0/201 1 ). Drugs such as acetylsalicylic acid, ibuprofen and paracetamol are on the WHO list of essential drugs in the non-steroidal anti-inflammatory class, and morphine and codeine have been included in the opioid analgesic class (WHO, 2010). However, these drugs have very limited utility in treating patients with painful conditions associated with neuropathies, conditions that represent a serious public health problem worldwide, and have a prevalence of between 7 and 8% in developed countries, where epidemiological studies have already been conducted. . Instead of these traditional drugs, gabapentin and pregabalin, anticonvulsant drugs, they have been approved in some countries for the treatment of patients with neuropathic pain. (TORRANCE, N. et al. 30 The epidemiology of chronic pain of predominantly neuropathic origin. survey J Pain, v. 7, no. 4, pp. 281-9, 2006. BOUHASSIRA, D. et al Prevalence of chronic pain with neuropathic characteristics in the general population. Pain, v. 136, no. 3, p. 380-7, 2008. DRAY, A. Neuropathic pain: emerging treatments. Br J Anaesth, v. 101, no. 1, p. 48-58, 2008. World Health Organization (WHO), 2010. Essential Medicines Lists <http://www.who.int/medicines/publications/ essentialmedicines / en / index.html> Accessed on 27 / 0/201 1 ).
Tetraciclinas quimicamente modificadas despertam grande interesse por apresentarem segurança potencialmente superior àquela de tetraciclinas convencionais. Esses fármacos não causariam candidíase nem distúrbios gastrintestinais, reações adversas associadas com o uso prolongado (duração média de 10,5 meses) do antibiótico HMCCI. Além disso, como substituições na periferia inferior do HMCCI (Figura 1 ) prejudicam a capacidade de quelação de cálcio(ll), outra vantagem potencial das tetraciclinas modificadas em relação ao HMCCI seria a possibilidade reduzida de deposição em ossos e indução de descoloração de dentes (prevalência de 3 a 6%), reações adversas atribuídas à formação de complexo entre HMCCI e ortofosfato de cálcio nesses tecidos (GOULDEN, V. et al. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol, v. 134, n. 4, p. 693-5, 1996. SANCHEZ, A. R. et al. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol, v. 43, n. 10, p. 709-15, 2004).  Chemically modified tetracyclines are of great interest because they are potentially more safe than conventional tetracyclines. These drugs would not cause candidiasis or gastrointestinal disorders, adverse reactions associated with prolonged use (average duration 10.5 months) of the antibiotic HMCCI. In addition, as substitutions at the lower periphery of HMCCI (Figure 1) impair calcium chelation ability (ll), another potential advantage of modified tetracyclines over HMCCI would be the reduced possibility of bone deposition and induction of tooth discolouration ( 3 to 6% prevalence), adverse reactions attributed to complex formation between HMCCI and calcium orthophosphate in these tissues (GOULDEN, V. et al. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol, v. 134, no. 4, pp. 693-5, 1996. SANCHEZ, AR Tetracycline and other tetracycline-derivative staining of teeth and oral cavity Int J Dermatol, v. 43, no. 709-15, 2004).
O pedido de patente W09626926 descreve a síntese de derivados 1 ,12-pirazoltetraciclinas e seu uso como antibióticos, porém não há relatos do uso desses derivados para o tratamento de dor.  Patent application WO9626926 describes the synthesis of 1,112-pyrazoltetracyclines derivatives and their use as antibiotics, but there are no reports of their use for pain management.
Lertvorachon e colaboradores descreveram a síntese de derivados hidroxipirazol da tetraciclina e HMCCI e suas atividades antioxidantes (LERTVORACHON, J. et al. 1 , 12-substituted tetracyclines as antioxidant agents. Bioorg Med Chem, v. 13, n. 15, p. 4627-37, 2005).  Lertvorachon and colleagues described the synthesis of hydroxypyrazole derivatives of tetracycline and HMCCI and their antioxidant activities (LERTVORACHON, J. et al., 1, 12-substituted tetracyclines as antioxidant agents. Bioorg Med Chem, v. 13, no. 15, p. 4627 -37, 2005).
Porém, não há relatos no estado da técnica do efeito antinociceptivo induzido pelo HPMCCI em modelos de dor neuropática. O uso de HPMCCI no tratamento de dor neuropática está associado a diversas vantagens, uma vez que os poucos medicamentos disponíveis para o tratamento de pacientes com doenças dessa natureza não são muito efetivos, associado ao fato de que o HPMCCI é potencialmente mais seguro que o HMCCI, uma vez que é desprovida de atividade antimicrobiana. However, there are no reports on the state of the art of HPMCCI-induced antinociceptive effect in neuropathic pain models. The use of HPMCCI in the treatment of neuropathic pain is associated with several advantages, since the few drugs available to treat patients with diseases of this nature are not very effective, associated with the fact that HPMCCI is potentially safer than HMCCI as it is devoid of antimicrobial activity.
DESCRIÇÃO DAS FIGURAS DESCRIPTION OF THE FIGURES
Figura 1 : Estrutura química do cloridrato de 1 1 ,12-pirazolminociclina (HPMCCI).  Figure 1: Chemical structure of 1,112-pyrazolminocycline hydrochloride (HPMCCI).
Figura 2: Espectro de massas por ESI no modo negativo do cloridrato de 1 1 ,12-pirazolminociclina (HPMCCI).  Figure 2: ESI mass spectrum in the negative mode 1,11-pyrazolocycline hydrochloride (HPMCCI).
Figura 3: Espectros eletrônicos do cloridrato de minociclina (HMCCI) em tampão TRIS 7,2 após adições sucessivas de CaC^ em tampão TRIS 7,2.  Figure 3: Electronic spectra of minocycline hydrochloride (HMCCI) in TRIS 7.2 buffer after successive additions of CaCl3 in TRIS 7.2 buffer.
Figura 4: Espectros eletrônicos do HPMCCI em tampão TRIS 7,2 após adições sucessivas de CaCl2. Figure 4: HPMCCI electronic spectra in TRIS 7.2 buffer after successive additions of CaCl 2 .
Figura 5: Efeito antinociceptivo induzido pelo HPMCCI, nas doses de 50 e 100 mg/Kg, no modelo de alodínia mecânica desenvolvida 10 dias após a constrição do nervo ciático em ratos. Os valores basais de limiar para retirada de pata foram determinados antes da cirurgia ou tratamento. No décimo dia após a cirurgia, os limiares foram determinados novamente, antes dos tratamentos.  Figure 5: HPMCCI-induced antinociceptive effect at doses of 50 and 100 mg / kg in the mechanical allodynia model developed 10 days after sciatic nerve constriction in rats. Baseline paw withdrawal thresholds were determined prior to surgery or treatment. On the tenth day after surgery, the thresholds were determined again before the treatments.
Figura 6 - Efeito induzido pelo cloridrato de 1 1 , 12-pirazolinominociclina (250 mg/kg, per os) sobre a alodínia avaliada 10 dias após a constrição de nervo ciático de ratos. * indica diferença estatisticamente significativa em relação ao grupo controle (p < 0,05). n=9 Figure 6 - Effect of 1,112-pyrazolinominocycline hydrochloride (250 mg / kg, per os) on allodynia evaluated 10 days after rat sciatic nerve constriction. * indicates statistically significant difference compared to the control group (p <0.05). n = 9
DESCRIÇÃO DETALHADA  DETAILED DESCRIPTION
A presente invenção compreende composições farmacêuticas contendo o composto cloridrato de 1 1 , 2-pirazolminociclina (HPMCCI) - um derivado da minociclina (HMCCI) - e excipientes farmaceuticamente aceitáveis, e seu uso para o alívio de dor neuropática.  The present invention comprises pharmaceutical compositions containing the 1,2-pyrazolminocycline hydrochloride compound (HPMCCI) - a minocycline derivative (HMCCI) - and pharmaceutically acceptable excipients, and their use for the relief of neuropathic pain.
Essas composições podem ser apresentadas nas formas: sólida, como comprimidos, drágeas, cápsulas e supositório; líquida, como soluções, suspensões e xaropes; bem como aerossóis, pastas, cremes, unguentos e loções para aplicação local ou como dispositivos transdérmicos. Sua administração pode ser realizada pelas vias oral, retal, intravenosa, intratecal, epidural ou tópica. Such compositions may be presented in solid forms such as tablets, pills, capsules and suppository; liquid, such as solutions, suspensions and syrups; as well as aerosols, pastes, creams, ointments and lotions for local application or as transdermal devices. Its administration can be by oral, rectal, intravenous, intrathecal, epidural or topical routes.
O HPMCCI pode ser utilizado isoladamente ou em associação com outros fármacos usualmente empregados no tratamento de pacientes portadores de dor neuropática, como os opioides (morfina, codeína, oxicodona, hidrocodona, tramadol), anti-inflamatórios não esteroidais (diclofenaco de sódio ou de potássio, ácido acetilsalicilico, paracetamol, ibuprofeno, cetroprofeno, naproxeno, flurbiprofeno), anticonvulsivantes usados no alívio de dor (carbamazepina, oxcarbazepina, gabapentina, pregabalina), antidepressivos usados no alívio de dor (amitriptilina, nortriptilina, fluoxetina, duloxetina) e medicamentos usados no tratamento de pacientes com artrite reumatóide (etanercepte, infliximabe, adalimumabe, certolizumabe, golimumabe, anakinra, rituximabe , abatacepte, tocilizumabe) e medicamentos usados na profilaxia de enxaqueca (propranolol, atenolol, metoprolol). HPMCCI can be used alone or in combination with other drugs commonly used to treat patients with neuropathic pain, such as opioids (morphine, codeine, oxycodone, hydrocodone, tramadol), non-steroidal anti-inflammatory drugs (diclofenac sodium or potassium). , acetylsalicylic acid, paracetamol, ibuprofen, cetroprofen, naproxen, flurbiprofen), pain relieving anticonvulsants (carbamazepine, oxcarbazepine, gabapentin, pregabalin), pain relieving antidepressants (amitriptyline, nortriptyline, fluoxetine) treatment of patients with rheumatoid arthritis (etanercept, infliximab, adalimumab, certolizumab, golimumab, anakinra, rituximab, abatacept, tocilizumab) and medicines used for prophylaxis of migraine (propranolol, atenolol, metoprolol).
A presente invenção apresenta, como vantagem, a ausência de atividade antibacteriana e antifúngica, possivelmente diminuindo os efeitos colaterais em comparação com HMCCI. Advantageously, the present invention has the absence of antibacterial and antifungal activity, possibly decreasing side effects compared to HMCCI.
A presente invenção pode ser mais bem entendida por meio dos seguintes exemplos, não limitantes, da tecnologia: The present invention may be better understood by the following non-limiting examples of technology:
Exemplo 1 : Preparação de HPMCCI Example 1: Preparation of HPMCCI
A obtenção de HPMCCI (Figura 1 ) foi realizada em duas etapas. Na primeira etapa foram adicionados 10 mmol de HMCCI e 15 mmol de hidrazina em 27 ml_ de uma solução metanol-isopropanol (1 :9). A solução foi mantida sob agitação e refluxo por 3 h. O produto obtido foi filtrado e seco sob pressão reduzida. Na segunda etapa, o sólido obtido foi recristalizado em 50 ml_ de benzeno para remover o isopropanol e favorecer a formação do anel pirazolínico, caso o produto não tivesse sido completamente formado. Opcionalmente, pode-se utilizar o diclorometano em substituição ao benzeno. A solução foi mantida sob agitação e aquecimento por 3 h, com reposição de benzeno quando necessário. O sólido obtido foi filtrado e seco sob pressão reduzida. O rendimento do produto após a segunda etapa variou entre 65 e 73%. Obtaining HPMCCI (Figure 1) was performed in two steps. In the first step 10 mmol of HMCCI and 15 mmol of hydrazine in 27 ml of a methanol-isopropanol solution (1: 9) were added. The solution was kept under stirring and reflux for 3 h. The product obtained was filtered and dried under reduced pressure. In the second step, the obtained solid was recrystallized from 50 ml of benzene to remove isopropanol and favor pyrazine ring formation if the product had not been completely formed. Optionally, dichloromethane may be used in place of benzene. The solution was kept under stirring and heating for 3 h with replacement of benzene when needed. The obtained solid was filtered and dried under reduced pressure. Product yield after the second step ranged from 65 to 73%.
Com o objetivo de confirmar a formação do produto desejado foram realizados espectros de massas por ionização por eletrospray (ESI) dos compostos. Na Tabela 1 estão apresentados os principais picos de m/z obtidos para o HMCCI e do seu derivado 1 1 , 2-pirazolínico, nos modos positivo e negativo. O espectro de massas por ESI no modo negativo de HPMCCI está apresentado na Figura 2.  In order to confirm the formation of the desired product, electrospray ionization (ESI) mass spectra of the compounds were performed. Table 1 shows the main m / z peaks obtained for HMCCI and its 1,2-pyrazolic derivative 11, in positive and negative modes. The HPMCCI negative mode ESI mass spectrum is shown in Figure 2.
Tabela 1 : Atribuição do principal pico de m/z obtidos para cloridrato de minociclina (HMCCI) e cloridrato de 1 1 , 12-pirazolminociclina (HPMCCI) por ESI, nos modos positivo e negativo (M = molécula).  Table 1: Assignment of the main peak m / z obtained for minocycline hydrochloride (HMCCI) and 1,112-pyrazolminocycline hydrochloride (HPMCCI) by ESI, in positive and negative modes (M = molecule).
HMCCI HMCCI
ESI(+)-MS ESI(-)-MS ESI (+) - MS ESI (-) - MS
Abundância Abundância Abundance Abundance
Ion m/z Ion m/z Ion m / z Ion m / z
relativa (%) relativa (%) relative (%) relative (%)
[M-CIf 458,41 100,00 [M-CI-2H]- 456,39 100,00 [M-CIf 458.41 100.00 [M-CIf 2H] - 456.39 100.00
H PMCCI H PMCCI
ESI(+)-MS ESI(-)-MS ESI (+) - MS ESI (-) - MS
Abundância Abundância Abundance Abundance
Ion m/z Ion m/z Ion m / z Ion m / z
relativa (%) relativa (%) relative (%) relative (%)
[M-Clf 454,39 100,00 [M-CI-2H]- 452,55 100,00 [M-Clf 454.39 100.00 [M-CI-2H] - 452.55 100.00
Exemplo 2: Avaliação da interação dos compostos HMCCI e HPMCCI com cálcio(ll) A capacidade dos compostos HMCCI e HPMCCI de interagirem com cálcio(ll) foi avaliada por meio da titulação espectrofotométrica envolvendo 3 ml_ de uma solução aquosa do composto em pH 7,2 (mantido pela solução tampão TRIS) com microadições de alíquotas de solução de cloreto de cálcio(ll). O sistema foi mantido a temperatura de 25 °C. Nas figuras 3 e 4 estão representados os espectros eletrônicos obtidos durante o experimento. Quando são comparados os espectros de HMCCI com os de HPMCCI pode-se observar que o deslocamento das bandas de absorção dos compostos para maiores energias, pode ser atribuído a formação do anel 1 1 ,12- pirazolínico, que ao ser formado leva à perda da transição π→π* atribuída à carbonila conjugada ao anel aromático D. Para HMCCI foi possível observar que ocorreu a interação com os íons cálcio(ll), o que já foi descrito na literatura (LERTVORACHON, J. ef ai. ,12-substituted tetracyclines as antioxidant agents. Bioorg Med Chem, v. 13, n. 15, p. 4627-37, 2005). Example 2: Evaluation of the interaction of HMCCI and HPMCCI compounds with calcium (11) The ability of the HMCCI and HPMCCI compounds to interact with calcium (11) was assessed by spectrophotometric titration involving 3 ml of an aqueous solution of the compound at pH 7. 2 (maintained by the TRIS buffer solution) with aliquots of calcium chloride solution (ll). The system was kept at 25 ° C. Figures 3 and 4 show the electronic spectra obtained during the experiment. When comparing the HMCCI spectra with those of HPMCCI it can be seen that the shifting of the absorption bands of the compounds to higher energies can be attributed to the formation of the 1,11-pyrazolic ring which, when formed, leads to loss of transition π → π * attributed to carbonyl conjugated to the aromatic ring D. For HMCCI it was possible to observe that interaction with calcium ions (II) occurred, which has already been described in the literature (LERTVORACHON, J. ef al., 12-substituted tetracyclines as antioxidant agents (Bioorg Med Chem, v. 13, no. 15, pp. 4627-37, 2005).
Exemplo 3: Avaliação da atividade antibacteriana  Example 3: Evaluation of antibacterial activity
Os primeiros testes de atividade antibacteriana foram realizados quantitativamente pelo método de macrodiluição em série. Os testes de atividade antibacteriana foram realizados seguindo os padrões do NCCLS (2002, 2003). Cepas de Staphylococus aureus (ATCC® 6538) e Pseudomonas aeruginosa (ATCC® 27853) foram inoculadas em caldo Mueller Hinton, sendo ambas incubadas a 37 °C por 18 a 24 h (PERNAK, J. et al. Synthesis and antimicrobial activities of new pyridinium and benzimidazolíum chlorides. Eur J Med Chem, v. 36, n. 4, p. 313-20, 2001 ). The first antibacterial activity tests were performed quantitatively by the serial macrodilution method. Antibacterial activity tests were performed following NCCLS standards (2002, 2003). Staphylococus aureus (ATCC ® 6538) and Pseudomonas aeruginosa (ATCC ® 27853) strains were inoculated into Mueller Hinton broth, both incubated at 37 ° C for 18 to 24 h (PERNAK, J. et al. Synthesis and antimicrobial activities of new pyridinium and benzimidazolum chlorides Eur J Med Chem, v. 36, no. 4, pp. 313-20, 2001).
A referência para a turbidez do inoculo foi medida pela análise do seu espectro de absorção na região do visível, nos comprimentos de onda 530 nm e 625 nm, devendo fornecer um valor de absorbância entre 0,08 e 0,1 , de forma que a concentração do inoculo é de 108 unidades formadoras de colónia (UFC). Foram retirados 100 μΐ_ do inoculo e transferidos para outro tubo contendo 9,9 ml_ de caldo Mueller Hinton, de modo que a concentração de inoculo neste tubo foi de 106 UFC. Foram acrescentados 200 μΙ_ deste inoculo aos tubos de diluição contendo 512, 256, 128, 64, 32, 16, 8, 4, 2, 1 , 0,5, 0,25, 0, 125, 0,062 e 0,031 pg/mL das substâncias testadas, de modo que a concentração de inoculo em cada tubo foi de 105 UFC. The reference for inoculum turbidity was measured by analyzing its absorption spectrum in the visible region at wavelengths 530 nm and 625 nm and should provide an absorbance value between 0.08 and 0.1, so that the The inoculum concentration is 10 8 colony forming units (CFU). 100 μΐ_ were taken from the inoculum and transferred to another tube containing 9.9 ml_ Mueller Hinton broth, so that the inoculum concentration in this tube was 10 6 CFU. 200 µl of this inoculum was added to the dilution tubes containing 512, 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0, 125, 0.062 and 0.031 pg / mL of the substances tested, so that the inoculum concentration in each tube was 10 5 CFU.
HMCCI foi utilizado como controle positivo nos testes feitos com o objetivo de avaliar a atividade do seu derivado contra S. aureus e P. aeruginosa. Após 20 h de incubação em estufa a 37 °C, foram determinadas as concentrações inibitórias mínimas (CIM) dos compostos.  HMCCI was used as a positive control in tests designed to evaluate the activity of its derivative against S. aureus and P. aeruginosa. After 20 h incubation at 37 ° C, the minimum inhibitory concentrations (MIC) of the compounds were determined.
Os valores para CIM dos compostos estão apresentados na Tabela 2. Tabela 2: Valores de CIM encontrados para HMCCI contra S. aureus ATCC' 6538 e P. aeruginosa ATCC® 9027 The MIC values of the compounds are shown in Table 2. Table 2: MIC values found for HMCCI against S. aureus ATCC '6538 and P. aeruginosa ATCC® 9027
CIM (pmol/l) MIC (pmol / l)
Composto  Compound
S. aureus P. aeruginosa  S. aureus P. aeruginosa
HMCCI 0, 108 3,35 HMCCI 0.108 3.35
HPMCCI >1082 > 1041 HPMCCI> 1082> 1041
Os valores de CIM estão de acordo com a faixa de valores apresentados esse composto frente a cepas de controle de qualidade. O aumento dos valores de CIM de HPMCCI, quando comparados com aqueles da tetraciclina de partida, podem ser atribuídos à formação do anel pirazolico com a presença dos nitrogênios ligados aos carbonos C 1 1 e C12, que levou à perda da atividade antibacteriana (SAIKALI, Z.; SINGH, G. Doxycycline and other tetracyclines in the treatment of bone metastasis. Anticancer Drugs, v. 14, n. 10, p. 773-8, 2003).  The MIC values are in accordance with the range of values presented for this compound against quality control strains. The increase in HPMCCI MIC values, when compared with those of the starting tetracycline, may be attributed to the pyrazole ring formation with the presence of carbon-bound nitrogen C 1 1 and C12, which led to the loss of antibacterial activity (SAIKALI, Z .; SINGH, G. Doxycycline and other tetracyclines in the treatment of bone metastasis (Anticancer Drugs, v. 14, no. 10, pp. 773-8, 2003).
Uma segunda bateria de testes foi realizada, utilizando-se noventa amostras clínicas: 30 de Staphylococcus aureus, 30 de Staphylococcus spp. coagulase-negativa e 30 de Escherichia coli. As linhagens eram sensíveis a uma ampla faixa de medicamentos antibacterianos, como demonstrado em teste conduzido de acordo com o método proposto pelo Clinicai Laboratories Standards Institute (CLSI , 201 1 ).  A second battery of tests was performed using ninety clinical samples: 30 Staphylococcus aureus, 30 Staphylococcus spp. negative coagulase and 30 of Escherichia coli. The strains were sensitive to a wide range of antibacterial drugs, as demonstrated in a test conducted according to the method proposed by the Clinical Laboratories Standards Institute (CLSI, 2011).
As concentrações inibitórias mínimas (CIM) de minociclina e HPMCCI foram avaliadas por meio do método de diluição em ágar (CLSI , 201 1 ). Soluções estoque das drogas foram adicionadas ao ágar Muller-Hinton (BD Difco™, EUA) levando a concentrações finais de 0, 125 a 64 pg/mL. Inóculos bacterianos foram preparados por suspensão direta da colónia em salina para obter uma densidade equivalente ao padrão 0,5 McFarland (aproximadamente 1 x 108 unidades formadoras de colônia/mL) e então inoculados em ágar Muller-Hinton com as drogas, usando um replicador Steers (Steers, Foltz et al. , 1959). As linhagens de referência de Staphylococcus aureus (ATCC® 25923) Staphylococcus epidermidis (ATCC® 12228) e Escherichia coli (ATCC® 25922) foram incluídos como controle. A CIM foi considerada a concentração mais baixa suficiente para inibir crescimento bacteriano seguindo normas do instituto CLSI (201 1 ). Minimal inhibitory concentrations (MIC) of minocycline and HPMCCI were assessed by the agar dilution method (CLSI, 201 1). Drug stock solutions were added to Muller-Hinton agar (BD Difco ™, USA) leading to final concentrations of 0.125 to 64 pg / mL. Bacterial inocula were prepared by direct suspension of the colony in saline to obtain a density equivalent to the 0.5 McFarland standard (approximately 1 x 10 8 colony-forming units / mL) and then inoculated onto the Muller-Hinton agar with the drugs using a replicator. Steers (Steers, Foltz et al., 1959). Staphylococcus aureus (ATCC® 25923) reference strains Staphylococcus epidermidis (ATCC® 12228) and Escherichia coli (ATCC® 25922) were included as a control. The MIC was considered the lowest concentration sufficient to inhibit bacterial growth following CLSI standards (201 1).
Nenhuma das linhagens bacterianas testadas foi sensível a HPMCCI na faixa de concentração usada. Como esperado, todas as linhagens foram sensíveis à minociclina (Tabela 3).  None of the bacterial strains tested was sensitive to HPMCCI in the concentration range used. As expected, all strains were sensitive to minocycline (Table 3).
Tabela 3: Concentrações inibitórias mínimas (pg/mL) da minociclina e de HPMCCI contra diferentes linhagens bacterianas  Table 3: Minimal inhibitory concentrations (pg / mL) of minocycline and HPMCCI against different bacterial strains
Staphylococcus aureus  Staphylococcus aureus
Número de linhagens resistentes*  Number of resistant strains *
(n=30)  (n = 30)
Concentrações (pg/mL) 0, 125 0,25 0,25 1 2 4* 8 16 32 64 Concentrations (pg / mL) 0.125 0.25 0.25 1 2 4 * 8 16 32 64
HMCCI 2 1 0 0 0 0 0 0 0 0HMCCI 2 1 0 0 0 0 0 0 0 0 0
Compostos Compounds
HPMCCI 30 30 30 30 30 30 30 30 30 30  HPMCCI 30 30 30 30 30 30 30 30 30 30 30
Staphylococcus spp. coagulase negativo Número de linhagens resistentes* Staphylococcus spp. negative coagulase Number of resistant strains *
(n=30) (n = 30)
Concentrações (pg/mL) 0, 125 0,25 0,25 1 2 4 8 16 32 64  Concentrations (pg / mL) 0.125 0.25 0.25 1 2 4 8 16 32 64
HMCCI 0 0 0 0 0 0 0 0 0 0 HMCCI 0 0 0 0 0 0 0 0 0 0 0
Compostos Compounds
HPMCCI 30 30 30 30 30 30 30 30 30 30  HPMCCI 30 30 30 30 30 30 30 30 30 30 30
Escherichia coli (n=30) Número de linhagens resistentes* Escherichia coli (n = 30) Number of resistant strains *
Concentrações (pg/mL) 0, 125 0,25 0,25 1 2 4 8 16 32 64 Concentrations (pg / mL) 0.125 0.25 0.25 1 2 4 8 16 32 64
HMCCI 9 4 0 0 0 0 0 0 0 0HMCCI 9 4 0 0 0 0 0 0 0 0 0
Compostos Compounds
HPMCCI 30 30 30 30 30 30 30 30 30 30 HPMCCI 30 30 30 30 30 30 30 30 30 30 30
*As bactérias testadas são consideradas sensíveis ao HMCCI quando apresentam seu crescimento inibido em concentração igual ou inferior a 16 pg/mL, CLSI 201 1. * The bacteria tested are considered sensitive to HMCCI when their growth inhibited at a concentration of 16 pg / mL or less, CLSI 201 1.
Exemplo 4: Avaliação da atividade antifúngica de HPMCCI Onze linhagens de Cândida albicans foram incluídas neste estudo. Todas as amostras foram mantidas em ágar Sabouraud dextrose a 4°C. Antes do teste, as amostras foram transferidas para um novo tubo contendo ágar Sabouraud dextrose a 37 °C por 24 h. As suspensões de fungos foram preparadas em solução salina (0,85% de cloreto de sódio, m/v) e a transmitância foi ajustada para 85% a 530 nm em um espectrofotômetro. A suspensão resultante (1 a 5 X 106 unidades formadoras de colônia/mL) foi agitada em um vórtex por 15 s e a densidade celular foi ajustada para 1 a 5 X 03 unidades formadoras de colônia/mL em meio RPMI-1640 (Inlab, Brasil). Example 4: Evaluation of HPMCCI Antifungal Activity Eleven Candida albicans strains were included in this study. All samples were kept on Sabouraud dextrose agar at 4 ° C. Prior to testing, samples were transferred to a new tube containing Sabouraud dextrose agar at 37 ° C for 24 h. Fungi suspensions were prepared in saline (0.85% sodium chloride, m / v) and the transmittance was adjusted to 85% at 530 nm on a spectrophotometer. The resulting suspension (1 to 5 X 10 6 colony forming units / mL) was vortexed for 15 h and cell density was adjusted to 1 to 5 X 0 3 colony forming units / mL in RPMI-1640 medium (Inlab, Brazil).
O ensaio de microdiluição foi conduzido usando meio RPMI-1640 esterilizado e tamponado com ácido morfolinopropanossulfônico (0, 165 mol/L, Sigma-Aldrich, EUA) como meio para teste. As soluções contendo cada uma das drogas testadas foram dissolvidas em água destilada e esterilizada. Então, foi feita diluição seriada em RPMI-1640, obtendo-se, finalmente, uma faixa de concentração de 128 a 0,25 pg/mL  The microdilution assay was conducted using sterile RPMI-1640 medium buffered with morpholinopropanesulfonic acid (0.155 mol / L, Sigma-Aldrich, USA) as the test medium. The solutions containing each of the drugs tested were dissolved in distilled and sterile water. Then, serial dilution in RPMI-1640 was performed, finally obtaining a concentration range of 128 to 0.25 pg / mL.
Alíquotas de cada diluição (100 μΙ_) foram distribuídas em placas para microdiluição com 96 poços com fundo plano, e, então, foram acrescentados 100 μΙ_ de suspensão dos inóculos. Controles foram também conduzidos para esterilização e crescimento. As placas foram incubadas a 37 °C por 24 h. Os testes foram feitas em duplicata para cada uma das diferentes concentrações. Aliquots of each dilution (100 μΙ_) were distributed into 96-well flat-bottom microdilution plates, and then 100 μΙ_ of inoculum suspension was added. Controls were also conducted for sterilization and growth. The plates were incubated at 37 ° C for 24 h. The tests were done in duplicate for each of the different concentrations.
Os resultados foram expressos em ng/mL, e a CIM foi definida visualmente como a concentração mais baixa capaz de inibir o crescimento fúngico, quando comparado com o grupo controle. Para fluconazol (controle positivo), a CIM foi aquela capaz de inibir 80% do crescimento fúngico (NCCLS, 2002).  Results were expressed in ng / mL, and MIC was visually defined as the lowest concentration capable of inhibiting fungal growth when compared to the control group. For fluconazole (positive control), the MIC was capable of inhibiting 80% of fungal growth (NCCLS, 2002).
Nenhuma das linhagens fúngicas testadas foi sensível à HPMCCI na faixa de concentração usada (até 128 pg/mL). Por outro lado, todas as linhagens foram sensíveis à minociclina em concentração alta (64 a 128 pg/mL) e ao fluconazol em concentração muito baixa (≤ 8 pg/mL), como esperado para um medicamento antifúngico usado como controle positivo (Tabela 4). Tabela 4: Concentrações inibitórias mínimas (pg/mL) de HPMCCI, HMCCI e fluconazol contra diferentes linhagens fúngicas None of the fungal strains tested was sensitive to HPMCCI in the concentration range used (up to 128 pg / mL). On the other hand, all strains were sensitive to high concentration minocycline (64 to 128 pg / mL) and very low concentration fluconazole (≤ 8 pg / mL), as expected for an antifungal drug used as a positive control (Table 4 ). Table 4: Minimum inhibitory concentrations (pg / mL) of HPMCCI, HMCCI and fluconazole against different fungal strains
Cândida albicans HPMCCI HMCCI fluconazol  Candida albicans HPMCCI HMCCI fluconazole
ATCC 8804 >128 64 2 ATCC 8804> 128 64 2
038-SBBO >128 64 1  038-SBBO> 128 64 1
093-SBBORG >128 128 2  093-SBBORG> 128 128 2
064-CHBOVD >128 64 4  064-CHBOVD> 128 64 4
030-CHBOVD >128 64 4  030-CHBOVD> 128 64 4
022-CHBOVD >128 64 8  022-CHBOVD> 128 64 8
1 1 1 -CHBOVD >128 64 1  1 1 1 -CHBOVD> 128 64 1
073-CHVGVD >128 64 4  073-CHVGVD> 128 64 4
031 -CHBOVD >128 64 4  031 -CHBOVD> 128 64 4
072-CHBOVD >128 64 2  072-CHBOVD> 128 64 2
024-CHBOVD >128 64 0,5  024-CHBOVD> 128 64 0.5
MIC 50* >128 64 2 MIC 50 * > 128 64 2
MIC 90** >128 64 4 MIC 90 ** > 128 64 4
* CIM que inibiu o crescimento de 50% ou ** 90% das linhagens testadas. * MIC that inhibited growth of 50% or ** 90% of the tested strains.
Exemplo 5: Avaliação da alodínia mecânica induzida pela constrição do nervo ciático em ratos Example 5: Evaluation of mechanical allodynia induced by sciatic nerve constriction in rats
Os procedimentos cirúrgicos de constrição do nervo são baseados na técnica descrita por Bennett e Xie, 1988 (BENNETT, G. J.; XIE, Y. K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, v. 33, n. 1 , p. 87-107, 1988).  Surgical nerve constriction procedures are based on the technique described by Bennett and Xie, 1988 (BENNETT, GJ; XIE, YK. Peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, v. 33, n 1, pp. 87-107, 1988).
Os animais foram anestesiados com isoflurano em oxigénio. Após a anestesia, por meio de uma incisão na região do bíceps femoral previamente tricotomizada e higienizada com iodopolividona 10% m/v, uma porção do nervo ciático foi exposta. Foram feitas quatro ligaduras com fio catgut cromado 4.0, com espaço de aproximadamente 1 mm entre elas. A força de constrição foi exercida de forma a não impedir a circulação sanguínea pela vasculatura superficial epineural. Um grupo controle foi composto por animais submetidos a uma falsa cirurgia, na qual o nervo não foi constringido, apenas visualizado. Os animais falso-operados ou operados foram tratados com o composto ou veículo (solução fisiológica) no décimo dia após a constrição do nervo. A avaliação do efeito induzido pelo composto foi realizada 2, 4 e 6 h após a administração. Animals were anesthetized with isoflurane in oxygen. After anesthesia, through an incision in the previously trichotomized femoral biceps region and sanitized with 10% m / v iodopolividone, a portion of the sciatic nerve was exposed. Four ligatures were made with catgut 4.0 chrome wire, with a gap of approximately 1 mm between them. The constriction force was exerted so as not to impede blood circulation through the vasculature. superficial epineural. A control group consisted of animals undergoing false surgery, in which the nerve was not constricted, only visualized. False or operated animals were treated with the compound or vehicle (physiological solution) on the tenth day after nerve constriction. Evaluation of the compound-induced effect was performed 2, 4 and 6 h after administration.
A alodínia mecânica foi avaliada por meio do uso de um analgesímetro digital. Esse equipamento permite a determinação do limiar para a retirada da pata e a resposta é expressa em gramas. Uma ponteira de plástico, acoplada a um braço transdutor (faixa: 0, 1 a 1000 g, ou aproximadamente 0,1 a 10 N), é aplicada sob o centro da superfície plantar da pata posterior direita dos animais colocados sobre uma grade. Quando a pata é pressionada gradualmente de baixo para cima, ocorre retirada da pata e o resultado então aparece no visor do analgesímetro. O limiar para essa resposta foi determinado cinco vezes, com intervalo de ao menos 20 s entre as determinações, e, então, o valor médio das medidas foi calculado.  Mechanical allodynia was assessed using a digital analgesometer. This equipment allows the determination of the paw withdrawal threshold and the response is expressed in grams. A plastic tip, coupled to a transducer arm (range: 0, 1 to 1000 g, or approximately 0.1 to 10 N), is applied under the center of the plantar surface of the right hind leg of the animals placed on a grid. When the paw is gradually depressed from the bottom up, paw withdrawal occurs and the result then appears on the analgesometer display. The threshold for this response was determined five times, with an interval of at least 20 s between determinations, and then the mean value of the measurements was calculated.
Na figura 4 estão apresentadas as curvas de limiar para retirada da pata direita em função do tempo após a administração intraperitoneal (i.p.) do composto HPMCCI ou do seu veículo em ratos submetidos à cirurgia de constrição do nervo ciático ou à falsa cirurgia.  Figure 4 shows the threshold curves for right paw withdrawal as a function of time after intraperitoneal (i.p.) administration of the HPMCCI compound or its vehicle in rats undergoing sciatic nerve constriction surgery or false surgery.
Observou-se efeito antinocicepivo induzido pelo HPMCCI (50 e 100 mg/Kg) 10 dias após a constrição do nervo ciático em ratos (n= 6 a 7/grupo). Os resultados foram expressos como média ± erro padrão da média. Foi feita análise de variância de medidas repetidas de duas vias, sendo tempo e tratamento os efeitos principais. O teste post hoc Bonferroni foi usado. * estatisticamente significativo com relação ao grupo operado e tratado com o veículo (p < 0,05).  HPMCCI-induced antinociceptive effect (50 and 100 mg / kg) was observed 10 days after sciatic nerve constriction in rats (n = 6 to 7 / group). Results were expressed as mean ± standard error of the mean. Two-way repeated measures analysis of variance was performed, with time and treatment as the main effects. The Bonferroni post hoc test was used. * statistically significant in relation to the operated and vehicle treated group (p <0.05).
O composto induziu efeito nesse modelo de dor neuropática, pois o limiar para retirada da pata ao estímulo mecânico foi elevado na segunda hora nos grupos operados tratados com composto (50 e 100 mg/kg) quando comparado com o grupo tratado com o veículo. Por outro lado, o grupo de animais falso-operados tratado com o composto (100 mg/kg) não teve o limiar para retirada de pata alterado em relação ao grupo falso-operado tratado com o veículo. Isso indica claramente que o composto inibe dor neuropática experimental. Compound had an effect on this neuropathic pain model, as the threshold for paw withdrawal to mechanical stimulation was elevated at the second hour in the compound-treated operated groups (50 and 100 mg / kg) when compared with the vehicle-treated group. On the other hand, the compound-treated sham-operated group (100 mg / kg) did not have the paw withdrawal threshold changed compared to the compound-treated sham-operated group. the vehicle. This clearly indicates that the compound inhibits experimental neuropathic pain.
Exemplo 6: Efeito antinociceptivo de HPMCCI administrado per os.  Example 6: Antinociceptive effect of HPMCCI administered per os.
O efeito antinociceptivo de HPMCCI administrado per os é de grande importância em um contexto terapêutico, pois a via oral é a mais cómoda para administração de medicamentos.  The antinociceptive effect of HPMCCI administered per os is of great importance in a therapeutic context, as oral administration is the most convenient for drug administration.
A Figura 6 apresenta dados relativos ao efeito antialodínico de HPMCCI administrado per os, o que pode ser atingindo aumentando-se em 5 vezes a dose eficaz administrada por via intraperitoneal (de 50 para 250 mg/kg). A cirurgia foi realizada como previamente descrito no Exemplo 5, e a droga foi administrada através de uma gavagem, em volume de 2 mL/kg, em solução salina contendo 5% de sacarose m/v (Labsynth®, Diadema, Brasil). Figure 6 shows data on the antiallodynamic effect of per os administered HPMCCI, which can be achieved by increasing the intraperitoneally administered effective dose by 5-fold (from 50 to 250 mg / kg). Surgery was performed as previously described in Example 5, and the drug was administered by gavage, in a volume of 2 mL / kg, in saline containing 5% sucrose m / v (Labsynth ® , Diadema, Brazil).

Claims

REIVINDICAÇÕES
1. COMPOSIÇÕES FARMACÊUTICAS PARA ALÍVIO DE DOR DE ORIGEM NEUROPATICA, caracterizadas por conterem o composto cloridrato de 1 , 12-pirazolminociclina e excipientes farmaceuticamente aceitáveis.  1. NEUROPATIC PAIN RELIEF PHARMACEUTICAL COMPOSITIONS, characterized in that they contain the 1,112-pyrazolocycline hydrochloride compound and pharmaceutically acceptable excipients.
2. COMPOSIÇÕES FARMACÊUTICAS PARA ALÍVIO DE DOR DE ORIGEM NEUROPATICA, de acordo com a reivindicação 1 , caracterizadas por apresentarem ausência de atividade antibacteriana e antifúngica. PHARMACEUTICAL COMPOSITIONS FOR NEUROPATIC PAIN RELIEF according to claim 1, characterized in that they have no antibacterial and antifungal activity.
3. COMPOSIÇÕES FARMACÊUTICAS PARA ALÍVIO DE DOR DE ORIGEM NEUROPATICA, de acordo com as reivindicações 1 e 2, caracterizadas por serem utilizadas individualmente ou em combinação com outros fármacos usualmente empregados no tratamento de pacientes portadores de dor neuropática, como os opioides (morfina, codeína, oxicodona, hidrocodona, tramadol), anti-inflamatórios não esteroidais (diclofenaco de sódio ou de potássio, ácido acetilsalicílico, paracetamol, ibuprofeno, cetroprofeno, naproxeno, flurbiprofeno), anticonvulsivantes usados no alívio de dor (carbamazepina, oxcarbazepina, gabapentina, pregabalina), antidepressivos usados no alívio de dor (amitriptilina, nortriptilina, fluoxetina, duloxetina), medicamentos usados no tratamento de pacientes com artrite reumatóide (etanercepte, infliximabe, adalimumabe, certolizumabe, golimumabe, anakinra, rituximabe, abatacepte, tocilizumabe) e medicamentos usados na profilaxia de enxaqueca (propranolol, atenolol, metoprolol).  PHARMACEUTICAL COMPOSITIONS FOR NEUROPATIC PAIN RELIEF according to Claims 1 and 2, characterized in that they are used individually or in combination with other drugs commonly used to treat patients with neuropathic pain, such as opioids (morphine, codeine , oxycodone, hydrocodone, tramadol), non-steroidal anti-inflammatory drugs (sodium or potassium diclofenac, acetylsalicylic acid, paracetamol, ibuprofen, cetroprofen, naproxen, flurbiprofen), anticonvulsants used for pain relief (carbamazepine, gababalapine, oxabalbazine, pregabalin, , pain relieving antidepressants (amitriptyline, nortriptyline, fluoxetine, duloxetine), medicines used to treat patients with rheumatoid arthritis (etanercept, infliximab, adalimumab, certolizumab, golimumab, anakinra, rituximab, abatacepte profilizuma, and tociluma) of migraine (propranolol, atenolol, metoprolol).
4. COMPOSIÇÕES FARMACÊUTICAS PARA ALÍVIO DE DOR DE ORIGEM NEUROPÁTICA, de acordo com as reivindicações 1 a 3, caracterizadas por serem apresentadas nas formas sólida, como comprimidos, drágeas, cápsulas e supositório; líquida, como soluções, suspensões e xaropes; bem como aerossóis, pastas, cremes, unguentos e loções para aplicação local ou como dispositivos transdérmicos.  PHARMACEUTICAL COMPOSITIONS FOR NEUROPATHIC PAIN RELIEF according to claims 1 to 3, characterized in that they are presented in solid forms, such as tablets, dragees, capsules and suppository; liquid, such as solutions, suspensions and syrups; as well as aerosols, pastes, creams, ointments and lotions for local application or as transdermal devices.
5. COMPOSIÇÕES FARMACÊUTICAS PARA ALÍVIO DE DOR DE ORIGEM NEUROPÁTICA, de acordo com as reivindicações 1 a 4, caracterizadas por poderem ser administradas pelas vias oral, retal, intravenosa, intratecal, epidural ou tópica. PHARMACEUTICAL COMPOSITIONS FOR NEUROPATHIC PAIN RELIEF according to Claims 1 to 4, characterized in that they can be administered by oral, rectal, intravenous, intrathecal, epidural or topical routes.
6. USO DAS COMPOSIÇÕES FARMACÊUTICAS, de acordo com as reivindicações 1 a 5, caracterizado por ser na preparação de medicamentos para tratamento de pacientes que apresentam dor de origem neuropática. USE OF PHARMACEUTICAL COMPOSITIONS according to Claims 1 to 5, characterized in that they are for the preparation of medicaments for the treatment of patients with neuropathic pain.
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