WO2012139191A1 - Compositions pharmaceutiques contenant de la 11,12-pyrazolminocycline et leur utilisation pour atténuer la douleur d'origine neuropathique - Google Patents

Compositions pharmaceutiques contenant de la 11,12-pyrazolminocycline et leur utilisation pour atténuer la douleur d'origine neuropathique Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
pharmaceutical compositions
neuropathic pain
minocycline
pain relief
drugs
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PCT/BR2012/000112
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English (en)
Portuguese (pt)
Inventor
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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Publication of WO2012139191A1 publication Critical patent/WO2012139191A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally 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).

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Abstract

La présente invention concerne des compositions pharmaceutiques contenant le composé chlorhydrate de 11,12-pyrazolminocycline (HPMCCI), un dérivé de la minocycline (HMCCI), ainsi que des excipients pharmaceutiquement acceptables, et leur utilisation pour atténuer la douleur neuropathique. La composition contenant du HPMCCI peut être utilisée de manière isolée ou en association avec d'autres médicaments pour le traitement de patients souffrant de douleur neuropathique. Le composé HPMCCI ne présente pas d'effet antimicrobien, ce qui, en comparaison avec la minocycline, peut réduire les réactions indésirables, d'où une meilleure adhésion des patients au traitement.
PCT/BR2012/000112 2011-04-15 2012-04-13 Compositions pharmaceutiques contenant de la 11,12-pyrazolminocycline et leur utilisation pour atténuer la douleur d'origine neuropathique WO2012139191A1 (fr)

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BR014110001295 2011-04-15
BRPI1106121-9 2011-11-25
BRPI1106121A BRPI1106121A2 (pt) 2011-11-25 2011-11-25 composições farmacêuticas contendo 11, 12-pirazolminociclina e uso para alívio de dor de origem neuropática

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1996026926A1 (fr) * 1995-02-28 1996-09-06 Biochimica Opos S.P.A. Pyrazolotetracyclines
WO2005082860A1 (fr) * 2004-02-27 2005-09-09 National Research Council Of Canada Tetracyclines et leur utilisation en tant qu'inhibiteurs de la calpaine
WO2006047756A2 (fr) * 2004-10-25 2006-05-04 Paratek Pharmaceuticals, Inc. Composes de tetracycline substitues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026926A1 (fr) * 1995-02-28 1996-09-06 Biochimica Opos S.P.A. Pyrazolotetracyclines
WO2005082860A1 (fr) * 2004-02-27 2005-09-09 National Research Council Of Canada Tetracyclines et leur utilisation en tant qu'inhibiteurs de la calpaine
WO2006047756A2 (fr) * 2004-10-25 2006-05-04 Paratek Pharmaceuticals, Inc. Composes de tetracycline substitues

Non-Patent Citations (2)

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Title
LEDEBOER, A ET AL.: "Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.", PAIN., vol. 115, 2005, pages 71 - 83, XP004844685, DOI: doi:10.1016/j.pain.2005.02.009 *
MIKA, J ET AL.: "Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain.", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 560, 2007, pages 142 - 149, XP005916810, DOI: doi:10.1016/j.ejphar.2007.01.013 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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