WO2015004634A2 - Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire - Google Patents

Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire Download PDF

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Publication number
WO2015004634A2
WO2015004634A2 PCT/IB2014/063019 IB2014063019W WO2015004634A2 WO 2015004634 A2 WO2015004634 A2 WO 2015004634A2 IB 2014063019 W IB2014063019 W IB 2014063019W WO 2015004634 A2 WO2015004634 A2 WO 2015004634A2
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WO
WIPO (PCT)
Prior art keywords
paracetamol
celecoxib
combination
further characterized
pharmaceutical
Prior art date
Application number
PCT/IB2014/063019
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English (en)
Spanish (es)
Other versions
WO2015004634A3 (fr
Inventor
Jorge Fernando CANTÚ MEDELLIN
Original Assignee
More Pharma Corporation, S. De R.L. De C.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by More Pharma Corporation, S. De R.L. De C.V. filed Critical More Pharma Corporation, S. De R.L. De C.V.
Priority to MX2015013911A priority Critical patent/MX366118B/es
Priority to CU2016000002A priority patent/CU24440B1/es
Publication of WO2015004634A2 publication Critical patent/WO2015004634A2/fr
Publication of WO2015004634A3 publication Critical patent/WO2015004634A3/fr
Priority to CR20160021A priority patent/CR20160021A/es

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Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention is part of the pharmaceutical field of the treatment of inflammatory pain. Specifically, the invention relates to a combination of paracetamol and celecoxib that has a synergistic effect in the treatment of inflammatory pain.
  • Inflammatory pain is a complex phenomenon characterized by spontaneous pain and hypersensitivity, which is caused in part at the level of the central nervous system. It is produced by the stimulation of nociceptors present in damaged tissue. It works as an alarm signal, so it has a protective biological function, although sometimes it can lead to a pathological state. This type of pain usually lasts a few days or a few weeks, and individuals will require medical care depending on the extent of such damage (Loeser JD, Melzack R; 1999, Pain: an overview. Pain. 353: 1607-1609). However, in certain inflammatory processes such as arthritis, the pain becomes chronic, which is highly debilitating for those who suffer from it and their quality of life is impaired.
  • Nonsteroidal anti-inflammatory analgesics have a high morbidity rate due to the toxicity they produce in the gastrointestinal tract, kidney and liver when administered chronically (Singh G, Triadafilopoulos G. 1999; Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl. 56: 18-24; Henry D, McGettigan P. 2003; Epidemiology overview of gastrointestinal and renal toxicity of NSAIDs. Int J Clin Pract Suppl.
  • Paracetamol is one of the most widely used drugs worldwide. Its analgesic effect has been proven in acute and chronic inflammatory pain in clinical studies (Cranswick N, Coghlan D; 2000. Paracetamol efficacy and safety in children: the first 40 years; Am J Ther. 7: 135-141) and preclinical (Bonnefont J, Alloui A, Chapuy E, Clottes E, Eschalier A; 2003. Orally administered paracetamol does not act locally in the rat formalin test: evidence for a supraspinal, serotonin-dependent antinociceptive mechanism. Anesthesiology. 99: 976-981). It has a good analgesic and antipyretic effect, but not a good anti-inflammatory effect.
  • celecoxib is a selective COX-2 enzyme inhibitor, indicated for acute pain due to trauma, osteoarthritis, other forms of acute arthritis and dysmenorrhea.
  • This drug entered the market as a pharmacological option in patients at high risk of developing toxicity at the level of the gastrointestinal tract by NSAIDs and in those who respond suboptimally or are intolerant to NSAIDs. (Gatti D, Adami S; 2010. Coxibs: a significant therapeutic opportunity. Acta Biomed. 81: 217-224).
  • celecoxib reduces acute and chronic pain in animals through the opioid and cannabinoid systems (Correa JD, Paiva-Lima P, Rezende RM, Dos Reis WG, Ferreira-Alves DL, Bakhle YS, Francischi JN; 2010. Peripheral mu-, kappa- and delta-opioid receptors measured the hypoalgesic effect of celecoxib in a rat model of thermal hyperalgesia; Life Sci.
  • compositions comprising a combination of an alkali metal or alkaline earth metal salt of acetaminophen (paracetamol) and another active ingredient selected from analgesics, decongestants, expectorants, cough suppressants, antihistamines, gastrointestinal agents, diuretics, bronchodilators and mixtures thereof.
  • paracetamol an alkali metal or alkaline earth metal salt of acetaminophen
  • Another active ingredient selected from analgesics, decongestants, expectorants, cough suppressants, antihistamines, gastrointestinal agents, diuretics, bronchodilators and mixtures thereof.
  • the object of this invention is to solve the problem of paracetamol solubility.
  • a dose range of paracetamol administration in humans is mentioned ranging from 80 to 1000 mg.
  • the additional active ingredient may be celecoxib (see page 8).
  • the present invention is directed precisely to solve the technical problem mentioned above, which has not been solved or even contemplated by the prior art.
  • the way in which the drawbacks of the prior art are solved is described below.
  • the present invention is based on the surprising finding that the combination of paracetamol and celecoxib in specific amounts generates an analgesic potentiation or synergy against inflammatory pain. This means that significantly smaller doses are needed to reach a certain level of analgesic effect.
  • the combination of the present invention comprises 375 mg of paracetamol and 50 to 75 mg of celecoxib.
  • the active ingredients of the combination can be administered separately, sequentially or concurrently.
  • Figure 1 is a dose-response graph showing the time course of the antinociceptive effect produced by oral administration of the vehicle (black circles) or the highest dose of paracetamol (white circles) evaluated in the present invention. (300 mg / Kg), in a study in rats with inflammatory pain induced by subcutaneous administration of 1% formalin.
  • Figure 2 is a dose-response graph showing the temporal course of the antinociceptive effect produced by oral administration of the vehicle (black circles) or the highest dose of celecoxib (white circles) evaluated in a study (10 mg / Kg), in rats with inflammatory pain induced by subcutaneous administration of 1% formalin.
  • Figure 3 is a dose-response graph showing the time course of the antinociceptive effect produced by oral administration of the vehicle (black circles) or the highest dose of the combination paracetamol + celecoxib (white circles) evaluated in a study (109.6 + 4.1 mg / kg, respectively), in rats with inflammatory pain induced by subcutaneous administration of 1% formalin.
  • Figure 4 contains dose-response graphs showing the percentage of antinociception obtained with oral administration of increasing doses of paracetamol during phase 1 (0-10 min) and phase 2 (10-60 min) of the formalin test. 1% in a study in rats. Data are expressed as the mean ⁇ the standard error of the mean of at least 6 animals per experimental group. * Statistically different from the vehicle with a p ⁇ 0.05 by one-way analysis of variance followed by Dunnett's test.
  • Figure 5 contains dose-response graphs showing the percentage of antinociception obtained with oral administration of increasing doses of celecoxib during phase 1 (0-10 min) and phase 2 (10-60 min) of the formalin test. 1% in a study in rats. Data are expressed as the mean ⁇ the standard error of the mean of at least 6 animals per experimental group. * Statistically different from the vehicle with a p ⁇ 0.05 by one-way analysis of variance followed by Dunnett's test.
  • Figure 6 is a dose-response graph showing the percentage of antinociception obtained with oral administration of increasing doses of the paracetamol plus celecoxib combination during phase 2 (10-60 min) of the 1% formalin test in a I study in rats. Data are expressed as the mean ⁇ the standard error of the mean of at least 6 animals per experimental group. * Statistically different from the vehicle with a p ⁇ 0.05 by one-way analysis of variance followed by Dunnett's test.
  • Figure 7 is an isobologram showing the interaction of potentiation or synergy obtained with the combination of paracetamol plus celecoxib administered orally (p.o.), in 1% formalin-induced inflammatory type pain in a study in rats.
  • the synergistic combination is formulated as a pharmaceutical composition.
  • Said pharmaceutical composition may be formulated for oral, rectal, intranasal, sublingual administration or for administration by intravenous, intramuscular or subcutaneous injection.
  • These formulations can be prepared by any of the procedures known in the pharmaceutical art. Therefore, in the case of compositions, they can be formulated as a liquid, suspension powder or elixir.
  • formulations for oral use they can be prepared in the form of tablets, tablets, soft gelatin capsules, hard capsules, syrups, aqueous or oily suspensions, dispersible powders or granules, emulsions, multiparticulate formulations, etc.
  • Other pharmaceutical compositions contemplated by the invention further include transdermal dosage forms, suppositories, powders or sprays for inhalation, and oral tablets.
  • the active ingredients may be mixed with inert excipients commonly used in the art, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredients are mixed with water or with miscible solvents.
  • inert excipients commonly used in the art, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredients are mixed with water or with miscible solvents.
  • miscible solvents such as for example propylene glycol, polyethylene glycol and ethanol, or an oily medium, such as olive oil or liquid paraffin.
  • the compounds of the invention can be formulated for parenteral administration for injection, for example, intravenous, intramuscular or subcutaneous injection.
  • Formulations for injection can be presented in single doses in, for example, ampoules or multi-dose containers, with an added preservative.
  • the compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and / or dispersing agents.
  • the active ingredient may be in powder form to reconstitute with a suitable vehicle, for example sterile pyrogen free water, before use.
  • the compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides.
  • Aqueous suspensions may include pharmaceutically acceptable excipients, such as suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, or gum arabic; dispersing or wetting agents such as natural phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecathylene ethylene oxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate,
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents or one or more sweetening agents, such as sucrose, saccharin or sodium or calcium cyclamate.
  • preservatives for example ethyl or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or sodium or calcium cyclamate.
  • sweetening agents such as sucrose, saccharin or sodium or calcium cyclamate.
  • Both paracetamol and celecoxib were suspended in isotonic saline with 10% Tween 80.
  • Individual or combination drugs were administered one hour before the algic stimulus, represented by subcutaneous injection of 1% formalin in the right hind leg of the rat.
  • the dose-response curves were analyzed by one-way analysis of variance followed by the Dunnet test. On the other hand, the statistical difference between the theoretical DE 50 and the experimental DE 50 was evaluated through a Student's t-test. The statistical difference of these tests was considered significant when it was obtained. a P ⁇ 0.05. Additionally, the type of interaction was determined by the interaction index ( ⁇ ), graphically and by comparing the confidence intervals of the theoretical DE 50 and the experimental DE 50 .
  • the interaction index if ⁇ is equal to 1 and / or its confidence interval crosses 1, the interaction is considered additive, however, if both ⁇ and its confidence interval are greater than 1, it is considered that the interaction is antagonistic and if both are less than 1, it is assumed that there is a potentiating or synergistic effect.
  • the point of the experimental DE 50 falls below the additive line, it is considered a potentiation or synergy effect, if it falls above it is antagonism, and if it falls on the additive line it is considered a summation effect.
  • Figures 1 -3 in black circles, show the typical time course that generates 1% subcutaneous injection of formalin in the dorsal region of the right hind leg of the rat (Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. 1992; The formalin test: an evaluation of the method. Pain. 51: 5-17).
  • the time course showed biphasic behavior.
  • Phase 1 started immediately after the administration of formalin and lasted for about 10 minutes (0-10 min), after this phase it followed a short period of time where nociceptive behavior manifestation was observed, and subsequently Phase two of the test began (10-60 min).
  • phase 2 the number of shocks gradually increased to a maximum between 25 and 30 minutes with a total duration of approximately 60 minutes.
  • Table 1 below shows the ED 50 obtained from the dose-response curves of paracetamol and celecoxib by linear regression.
  • Figure 5 shows the antinociceptive (analgesic) effect that produced celecoxib in a dose-dependent manner in both phases of the inflammatory pain model.
  • the equieffective doses were calculated at constant proportions of the paracetamol plus celecoxib combination.
  • the percentages of antinociception obtained with paracetamol and celecoxib during phase 2 of the formalin test were considered for the calculation of equieffective doses.
  • Phase 2 was chosen because in this phase the drugs reached more than 50% antinociceptive effect at the doses evaluated, and more importantly, because this phase simulates a painful condition that is caused by an inflammatory process in humans, which is relevant clinically, while phase 1 simulates a transient phasic pain, which has no clinical relevance since it does not require medical treatment.
  • Figure 6 shows the antinociceptive effect produced by the combination celecoxib and paracetamol in pain induced by 1% formalin. In this phase the combination produced an efficiency of 70.5% and an experimental ED 50 of 57.5 ⁇ 1.5 mg / kg.
  • the Student t test showed statistical difference with a p ⁇ 0.05 between theoretical and DE 50 DE 50 experimental.
  • the interaction index (v) showed a value below 1 (See Table 2 below).
  • the confidence interval of the interaction index does not cross by 1 (See Table 2 below).
  • the confidence interval of the experimental DE 50 does not overlap with the confidence interval of the theoretical DE 50 and its values are below the latter (See Table 2 below).
  • the finding of the present invention is explained based on Tables 1 and 2 and Figure 7 of the present application.
  • the theoretical SD 50 of 13.8 mg / kg (see table 2) constitutes the sum of half the amount of celecoxib plus half the amount of paracetamol, that is, (8.2 + 219.4) / 2 (see figure 7).
  • the quantities mentioned are in table 1.
  • the experimental ED 50 was 57.5 mg / kg (see table 2), that is, approximately 50% of the theoretical DE 50 .
  • the data of the experimental ED are supported in Figure 7 and are approximately 2 mg of celecoxib / Kg + 55.5 mg of paracetamol / Kg that give 57.5 mg / Kg.
  • the recommended daily average dose of paracetamol is between 250 and 1000 mg per day in adults and the maximum recommended dose is 4000 mg per day.
  • the recommended daily average dose of celecoxib is 100 to 200 mg every 12 hours, the maximum daily dose being 400 mg.
  • the specific combination proposed, according to the results of the isobolographic study, is a combination that includes 375 and 500 mg of paracetamol and between 50 and 100 mg of celecoxib, more specifically, 375 mg of paracetamol and between 50 and 75 mg of celecoxib, more preferably 375 mg of paracetamol and 50 mg of celecoxib, which provides an analgesic effect equivalent to individual doses of, for example, 500 mg of paracetamol with 100 mg of celecoxib with a very wide safety window (adverse effects).

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une combinaison de paracétamol et de célécoxib qui dans des quantités spécifiques génèrent un potentialisateur analgésique contre la douleur de type inflammatoire. Plus particulièrement, l'invention concerne une combinaison synergique qui comprend entre 375 à 500 mg de paracétamol et entre 50 à 100 mg de célécoxib utile dans le traitement de la douleur inflammatoire des animaux et des êtres humains, ainsi que l'utilisation de ces principes actifs dans les quantités indiquées pour la préparation de combinaisons pharmaceutiques synergiques.
PCT/IB2014/063019 2013-07-11 2014-07-11 Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire WO2015004634A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
MX2015013911A MX366118B (es) 2013-07-11 2014-07-11 Combinacion sinergistica de paracetamol/celecoxib para el tratamiento de dolor inflamatorio.
CU2016000002A CU24440B1 (es) 2013-07-11 2014-07-11 Composición farmacéutica de paracetamol/celecoxib para el tratamiento de dolor inflamatorio
CR20160021A CR20160021A (es) 2013-07-11 2016-01-11 Combinación sinergística de paracetamol/celecoxib para el tratamiento de dolor inflamatorio

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/IB2013/055710 WO2015004505A1 (fr) 2013-07-11 2013-07-11 Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire
IBPCT/IB2013/055710 2013-07-11

Publications (2)

Publication Number Publication Date
WO2015004634A2 true WO2015004634A2 (fr) 2015-01-15
WO2015004634A3 WO2015004634A3 (fr) 2015-04-09

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ID=52279400

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PCT/IB2013/055710 WO2015004505A1 (fr) 2013-07-11 2013-07-11 Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire
PCT/IB2014/063019 WO2015004634A2 (fr) 2013-07-11 2014-07-11 Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire

Family Applications Before (1)

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PCT/IB2013/055710 WO2015004505A1 (fr) 2013-07-11 2013-07-11 Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire

Country Status (8)

Country Link
CL (1) CL2015003211A1 (fr)
CR (1) CR20160021A (fr)
CU (1) CU24440B1 (fr)
DO (1) DOP2016000008A (fr)
EC (1) ECSP16005679A (fr)
MX (1) MX366118B (fr)
PE (2) PE20170305A1 (fr)
WO (2) WO2015004505A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11147780B2 (en) * 2020-02-24 2021-10-19 Algia Pharma, Llc Multidrug pain management package

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
OA12778A (en) * 2002-02-19 2006-07-06 Adcock Ingram Ltd Pharmaceutical combination of COX-2 inhibitors andipiates.
GB0423103D0 (en) * 2004-10-19 2004-11-17 Boots Healthcare Int Ltd Therapeutic agents

Also Published As

Publication number Publication date
WO2015004505A1 (fr) 2015-01-15
PE20170305A1 (es) 2017-04-21
MX366118B (es) 2019-06-27
ECSP16005679A (es) 2017-08-31
CL2015003211A1 (es) 2016-04-29
WO2015004634A3 (fr) 2015-04-09
CU20160002A7 (es) 2016-06-29
MX2015013911A (es) 2015-12-08
DOP2016000008A (es) 2016-03-15
CU24440B1 (es) 2019-09-04
PE20160239A1 (es) 2016-05-13
CR20160021A (es) 2016-04-08

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