WO2015016696A1 - Composition pharmaceutique pour le traitement de la douleur - Google Patents

Composition pharmaceutique pour le traitement de la douleur Download PDF

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Publication number
WO2015016696A1
WO2015016696A1 PCT/MX2014/000115 MX2014000115W WO2015016696A1 WO 2015016696 A1 WO2015016696 A1 WO 2015016696A1 MX 2014000115 W MX2014000115 W MX 2014000115W WO 2015016696 A1 WO2015016696 A1 WO 2015016696A1
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WO
WIPO (PCT)
Prior art keywords
inflammatory
pharmaceutically acceptable
acceptable salts
ketorolac
immediate
Prior art date
Application number
PCT/MX2014/000115
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English (en)
Spanish (es)
Inventor
Federico AMEZCUA AMEZCUA
Amador COVARRUBIAS PINEDO
Original Assignee
Laboratorio Raam De Sahuayo, S.A. 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
Publication date
Application filed by Laboratorio Raam De Sahuayo, S.A. De C.V. filed Critical Laboratorio Raam De Sahuayo, S.A. De C.V.
Publication of WO2015016696A1 publication Critical patent/WO2015016696A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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 relates to the novel synergistic combination of lysine and ketorolac acetylsalicylate and / or its pharmaceutically acceptable salts with a potential analgesic effect for use in the treatment of pain, inflammation, fever and / or related disorders .
  • a pharmaceutical composition comprising at least one delayed release and / or immediate release core containing lysine acetylsalicylate and / or ketorolac is described; and at least two layers of immediate and / or prolonged release containing ketorolac and / or lysine acetylsalicylate.
  • Pain can be defined as an unpleasant sensory and emotional experience associated with a real or potential tissue injury, this according to the International Association for the Study of Pain and can be classified in the following ways:
  • Acute pain it is the immediate consequence of the activation of the nociceptive system whose function is that of biological protection (alarm at the level of injured tissue).
  • Psychological symptoms are scarce and limited to mild anxiety. It is a pain of nociceptive nature and appears by chemical, mechanical or thermal stimulation of specific nociceptors with a temporary course that closely follows the process of repair and healing of the causal injury.
  • Chronic pain is one that persists beyond the injury that caused it to remain in the individual once that injury disappears. Generally, chronic pain is a symptom of a persistent disease whose evolution is continuous or in outbreaks and involves the presence of pain even in the absence of any peripheral lesion.
  • Somatic pain is one that affects the skin, muscles, joints, ligaments or bones; It is a well located pain, limited to the damaged area and clear and precise sensations.
  • Visceral pain is that caused by lesions that affect internal organs, so it is the form of pain that appears most frequently as a result of diseases. It is a vague pain, poorly located and that extends beyond the injured organs and is accompanied by intense motor and vegetative reflex reactions. (FORNIES A, 2006)
  • Nociceptive pain is that form of pain that appears in normal individuals as a result of the application of stimuli that cause damage or injury to somatic or visceral organs. It is the consequence of the activation of the neurophysiological system constituted by peripheral nociceptors, central pathways of the painful sensation and, finally, cerebral cortex. The intensity and duration of sensations of nociceptive pain depends crucially on the modulation of signals of tissue injury along the nociceptic pathway is always due to the activation of a specific sensory system responsible for its transmission.
  • Neuropathic pain it is the result of an injury or alteration of the transmission of nociceptive information at the level of the Central or Peripheral Nervous System.
  • neuropathic pains are those of spontaneous presentation in the absence of a causal lesion, pain threshold reductions and pain caused by touch and low intensity mechanical stimuli. (FORNIES A, 2006)
  • Nonsteroidal anti-inflammatory drugs NSAIDs
  • opioid analgesics opioid analgesics
  • adjuvant analgesics Nonsteroidal anti-inflammatory drugs
  • NSAIDs Nonsteroidal anti-inflammatory drugs
  • They constitute one of the most prescribed groups of drugs, they are a heterogeneous group of compounds, often not chemically related but that share therapeutic actions and adverse effects. They do not cause respiratory depression or induce tolerance or physical dependence.
  • Their analgesic efficacy is limited (ceiling effect) and they are not dose dependent (increasing the dose may prolong the effect, but it does not produce more analgesia and increases the incidence of side effects).
  • NSAIDs are effective for the treatment of mild-moderate pain, and in some cases they can control the severe pain of an inflammatory, post-surgical or colic component.
  • NSAIDs are: acetylsalicylic acid, sulindac, diclofenac, etodolac, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, naproxen, acetaminophen, lysine acetylsalicylate, COX 2 inhibitors, among others.
  • Opioid analgesics it is a group of drugs that act on opioid receptors, with different affinity to each receptor, their analgesic activity is the product of their union with a receptor, they produce drug dependence and cause psychological effects of variable characteristics and intensity.
  • Opioid analgesics oripavine, morphine, diphenylmethane, phenylpiperidine, anilinopiperidine, among others. (RODRIGUEZ A, 2002)
  • Adjuvant analgesics those whose main pharmacological action is not analgesia but which, due to their particular mechanism of action, are generally used in a complementary way in the treatment of pain. These analgesics increase the analgesic effect of narcotics, decrease their toxicity, reduce opioid requirements, improve various symptoms associated with painful syndromes, combat adverse effects of analgesics (antiemetics and laxatives), allowing pain relief and concomitant psychological disorders.
  • the adjuvant analgesics the following may be mentioned: tricyclic antidepressants, antihistamines, benzodiazepines, caffeine, dextroamphetamine, metocarbamol and clonidine (SILBERMAN E, 2001).
  • ketorolac and lysine acetylsalicylate belong to the family of non-steroidal analgesics (NSAIDs).
  • NSAIDs non-steroidal analgesics
  • a ketorolac synthesis method is described in US Patent 4,089,696, ketorolac is an arylpropionic compound that has a carboxylic acid group which binds to the site of action, a phenyl group and a flat structure formed by a nitrogen that confers stability in the binding to cyclooxygenase (COX), an enzymatic complex on which it acts.
  • COX cyclooxygenase
  • Cyclooxygenase is an enzyme that has two different isoforms (COX-1 and COX-2) and is responsible for synthesizing prostaglandins (PG) from arachidonic acid.
  • the tissues in which each isoform is expressed are different: COX-1 is a constitutive part of most cells in the body, among which parietal, cardiac, renal and epithelial cells stand out and aims to synthesize protective PG of the gastric mucosa of electrolytic homeostasis in case of hypovolemia, PG involved in vasodilation and facilitators of platelet aggregation.
  • COX-2 in addition to being constitutive in smaller quantities, is also induced by inflammatory processes, since in addition to the synthesis of prostaglandins, it is a catalyst for the production of prostacyclines and thromboxanes responsible for vasoconstriction / vasodilation regulation, sensitization of peripheral nociceptive receptors, fibrinolysis, etc.
  • the ketorolac being not selective for some isoforms, inhibits both the formation of pro-inflammatory PG and PG in peripheral nociceptors, that is, acts as an anti-inflammatory and analgesic in addition to promoting production of PG "protectors" from COX-1 (ZAVALETA M, 2007).
  • Lysine acetylsalicylate is a ' prodrug of acetylsalicylic acid belonging to the group of salicylates. Salification with lysine improves its bioavailability, registering a 300 percent increase in gastric absorption rate compared to acetylsalicylic acid and an increase in digestive tolerance in chronic treatments at high doses (8g / day, in a treatment of 3 months duration). Said compound is described in US Patent 4,265,888. It is indicated for the symptomatic relief of occasional mild or moderate pain, inflammation, febrile conditions, helps in the metabolism of uric acid, displaces thyroid hormones from their binding to plasma proteins and is a platelet antiaggregant. Its mechanism of action is based on the non-selective inhibition of cyclooxygenase (Mendoza, 2008).
  • lysine acetylsalicylate is associated with the inhibition of cyclooxygenase (COX), the main enzyme of arachidonic acid metabolism has its anti-inflammatory, analgesic and antipyretic effect.
  • Lysine acetylsalicylate is rapidly fragmented in plasma after absorption, giving rise to acetylsalicylic acid and lysine.
  • the Mexican peak reaches it 30-40 minutes after ingestion of the drug, without this being affected by the presence of food.
  • the elimination is carried out by hydrolysis of acetylsalicylic acid and by hepatic conjugation, which gives rise to inactive metabolites that, together with acetylsalicylic acid, are excreted by the kidneys. The elimination increases with the alkalinization of the urine.
  • compositions containing ketorolac and lysine clonixinate comprising a ketorolac core, a surface active agent, an alkaline agent (lysine) and a binding agent (US20040028735); an oral solution comprising ketorolac tromethamine and at least one amino acid as an excipient, may itself be lysine (WO2012054831); solution containing ketorolac, a compound of a basic nature and a salt of the trisubstituted lysine glycyric acid (EP1226831, US6699841 and US20020193322); multivesicular liposomes containing ketorolac and lysine as a pH modifier (O2012058483 and US20120114740); immediate and sustained release tablet consisting of a complex with a carboxy polymer with a multivalent cation, a disintegrating agent, a modul
  • the object of the invention is to provide a synergistic combination with analgesic, anti-inflammatory and potentialized antipyretic effect, useful for use in the prevention and / or treatment of mild, moderate or severe pain; furthermore, pharmaceutical compositions are described comprising at least one delayed release and / or immediate release core containing lysine acetylsalicylate and / or ketorolac; and at least two layers of immediate and / or prolonged release containing ketorolac and / or lysine acetylsalicylate.
  • the present invention relates to a synergistic combination with potential analgesic, anti-inflammatory and antipyretic effect comprising a) at least one non-steroidal anti-inflammatory and / or its pharmaceutically acceptable salts; and, b) at least one anti-inflammatory of the salicylate group.
  • a) is selected from at least one of the following non-steroidal anti-inflammatories: acetylsalicylic acid, sulindac, diclofenac, etodolac, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid , naproxen, acetaminophen and / or its pharmaceutically acceptable salts.
  • ketorolac and / or its pharmaceutically acceptable salts are used.
  • the synergistic combination described herein is characterized in that the anti-inflammatory of the group of salicylates b) is lysine acetylsalicylate and / or polymorphs thereof.
  • the present invention consists descriptively but not limited to various compositions comprising a) at least one non-steroidal anti-inflammatory and / or its pharmaceutically acceptable salts; b) at least one anti-inflammatory of the salicylate group; and, at least one pharmaceutically acceptable excipient.
  • the present invention relates to various pharmaceutical compositions for oral, topical and intramuscular administration, within which they are found in a non-limiting manner: tablet, sublingual tablet, chewable tablet, modified release tablet, soft and hard gelatin capsule, oral solution or injectable, topical gel, oral gel, ointment or ointment, powder and / or granule and / or effervescent tablet, pellet, liposome, among others.
  • the novel composition of the present invention mainly refers to a pharmaceutical system composed of the mixture of at least two NSAIDs mainly ketorolac and lysine acetyl salicylate contained in said pharmaceutical system.
  • Said pharmaceutical system comprises at least one delayed-release and / or immediate-release core that contains at least one non-steroidal anti-inflammatory and / or its pharmaceutically acceptable salts and / or at least one anti-inflammatory of the salicylate group; and at least two immediate and / or prolonged release layers containing at least one non-steroidal anti-inflammatory and / or its pharmaceutically acceptable salts and / or at least one anti-inflammatory of the salicylate group.
  • the pharmaceutical system preferably comprises at least one delayed release and / or immediate release core containing acetylsal lysine lysine and / or ketorolac; and at least two layers of immediate and / or prolonged release containing ketorolac and / or lysine acetylsalicylate.
  • the present invention can be prepared in the form of a composition
  • a composition comprising 1) a delayed and / or immediate release core containing at least one anti-inflammatory of the salicylate group, coated by 2) at least one lower immediate release layer and / or prolonged that contains at least one non-steroidal anti-inflammatory and / or its pharmaceutically acceptable salts and / or at least one anti-inflammatory of the salicylate group, and 3) an upper layer of immediate and / or prolonged release that contains at least one non-anti-inflammatory steroids and / or their pharmaceutically acceptable salts and / or at least one anti-inflammatory of the salicylate group.
  • the composition comprises 1) a delayed and / or immediate release core containing lysine acetylsalicylate, coated by 2) at least one first immediate and / or prolonged release layer containing ketorolac and / or its pharmaceutically acceptable salts and / or lysine acetylsalicylate, and 3) an upper immediate and / or prolonged release layer containing ketorolac and / or its pharmaceutically acceptable salts and / or lysine acetylsalicylate.
  • a further embodiment of the composition described in the present invention comprises 1) at least one delayed and / or immediate release core containing at least one anti-inflammatory of the salicylate group, coated by 2) a first immediate and / or first release layer prolonged containing at least one non-steroidal anti-inflammatory and / or its pharmaceutically acceptable salts and / or at least one anti-inflammatory from the salicylate group; and, 3) a second layer of immediate and / or prolonged release layer containing at least one non-steroidal anti-inflammatory and / or its pharmaceutically acceptable salts and / or at least one anti-inflammatory of the salicylate group.
  • the composition comprises 1) a delayed and / or immediate release core containing lysine acetylsalicylate, coated by 2) at least one lower and immediate or extended release lower layer containing ketorolac and / or its pharmaceutically acceptable salts and / or lysine acetylsalicylate, and 3) a second immediate and / or prolonged release layer containing ketorolac and / or its pharmaceutically acceptable salts and / or lysine acetyl ilsalicylate.
  • compositions of the present invention consist mainly of the combination of Ketorolac and lysine acetylsalicylate, where the lysine Ketorolac-acetylsalicylate mixture acts synergistically by potentiating the analgesic effect for pain treatment.
  • compositions described in the present invention are preferably used as a non-steroidal anti-inflammatory, ketorolac and / or its pharmaceutically acceptable salts in a range of 0.1 mg to 100 mg, and more preferably in a range of 1 mg to 50 mg; and lysine acetylsalicylate in a range of 1 mg to 500 mg, and more preferably in a range of 50 mg to 200 mg.
  • compositions described above contain at least one pharmaceutically acceptable excipient selected from the following group: release polymers, binder, lubricant, solvent, diluent, agent for modifying the solution, colorant, sweetener, gliding, solubility enhancing agent, disintegrant, superdisintegrant , among others.
  • the novel pharmaceutical composition comprises a core containing at least one non-steroidal anti-inflammatory and / or its salts pharmaceutically acceptable and / or at least one anti-inflammatory of the salicylate group, at least one diluent and / or at least one release polymer and / or at least one binder and / or at least one lubricant and / or at least one solvent.
  • the novel pharmaceutical composition comprises at least two layers containing at least one non-steroidal anti-inflammatory and / or its pharmaceutically acceptable salts and / or at least one anti-inflammatory of the salicylate group, at least one diluent and / or at least a binder and / or at least one disintegrant and / or at least one lubricant and / or at least one solvent.
  • the diluent useful for the present invention may be at least one excipient selected from: sucrose, microcrystalline mannitol cellulose, starch, lactose, sorbitol, glucose, calcium sulfate, dibasic and tribasic calcium phosphate, among others and / or combinations thereof .
  • release polymer may be at least one excipient selected from: 2- hydroxyethium polymethacrylate, polyvinyl alcohol, polyethylene glycol,
  • Methylcellulose metolose, polyethylene glycol-co -utylene terephthalate, acrylic polyacid, polyethacrylate coethylene glycol, among others and / or combinations thereof.
  • the binder can be at least one excipient selected from: pectin, gum tragacanth, starch.
  • the lubricant can be at least one excipient selected from: calcium stearate, fumaric acid, glycerol behenate, stearic acid, sodium lauryl sulfate, talc, starch, magnesium stearate, among others and / or combinations thereof.
  • the disintegrant can be at least one excipient selected from: alginic acid, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, aluminum silicate, polacrilin potassium, hydroxypropyl starch, 'pregelatinized etc. and / or combinations thereof.
  • the solvents can be polar and / or non-polar and are selected from the following group: acetone and / or ethanol and / or water and / or benzyl alcohol and / or combinations thereof.
  • compositions used during the development of the invention are described by way of illustrative, but not limited to:
  • Example 1 Solid composition with immediate release core and immediate release layers
  • Example 2 Solid composition with delayed release core and immediate release layers
  • the advantages of the present invention are: Synergistic combination for the prevention and treatment of pain.
  • Synergistic analgesic, anti-inflammatory and potentialized antipyretic effect Stable composition. Integral pain management. It does not produce dependence. Convenience of use for the patient. Effective and efficient composition.

Abstract

La présente invention concerne une combinaison synergique ayant un effet analgésique, anti-inflammatoire et antipyrétique potentialisé qui comprend a) au moins un anti-inflammatoire non stéroïdien et/ou ses sels pharmaceutiquement acceptables; y, b) au moins un anti-inflammatoire du groupe des salicylates. En outre, l'invention concerne une composition pharmaceutique qui comprend au moins un noyau à libération retardée et/ou à libération immédiate qui contient au moins un anti-inflammatoire non stéroïdien et/ou ses sels pharmaceutiquement acceptables et/ou au moins un anti-inflammatoire du groupe des salicylates; et au moins deux couches à libération immédiate et/ou prolongée qui contiennent au moins un anti-inflammatoire non stéroïdien et/ou ses sels pharmaceutiquement acceptables et/ou au moins un anti-inflammatoire du groupe des salicylates.
PCT/MX2014/000115 2013-08-02 2014-07-24 Composition pharmaceutique pour le traitement de la douleur WO2015016696A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX2013008995A MX2013008995A (es) 2013-08-02 2013-08-02 Composicion farmaceutica para el tratamiento del dolor.
MXMX/A/2013/008995 2013-08-02

Publications (1)

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WO2015016696A1 true WO2015016696A1 (fr) 2015-02-05

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WO (1) WO2015016696A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2293938A1 (fr) * 1974-12-12 1976-07-09 Richter Gedeon Vegyeszet Nouvelles compositions anti-inflammatoires et leur procede de preparation
US5316772A (en) * 1990-12-19 1994-05-31 Solvay & Cie, S.A. (Societe Anonyme) Bilayered oral pharmaceutical composition with pH dependent release
US6277362B1 (en) * 1999-10-26 2001-08-21 Isw, Inc. After shave treatment preparation
US20040077609A1 (en) * 2001-01-16 2004-04-22 Michael Rubin Oral composition containing NSAIDs and essential oils
WO2007103113A2 (fr) * 2006-03-06 2007-09-13 Pozen Inc. Formes pharmaceutiques pour l'administration d'associations de medicaments
US20080026054A1 (en) * 2007-04-27 2008-01-31 Nectid Inc. Novel anelgesic combination

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2293938A1 (fr) * 1974-12-12 1976-07-09 Richter Gedeon Vegyeszet Nouvelles compositions anti-inflammatoires et leur procede de preparation
US5316772A (en) * 1990-12-19 1994-05-31 Solvay & Cie, S.A. (Societe Anonyme) Bilayered oral pharmaceutical composition with pH dependent release
US6277362B1 (en) * 1999-10-26 2001-08-21 Isw, Inc. After shave treatment preparation
US20040077609A1 (en) * 2001-01-16 2004-04-22 Michael Rubin Oral composition containing NSAIDs and essential oils
WO2007103113A2 (fr) * 2006-03-06 2007-09-13 Pozen Inc. Formes pharmaceutiques pour l'administration d'associations de medicaments
US20080026054A1 (en) * 2007-04-27 2008-01-31 Nectid Inc. Novel anelgesic combination

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Publication number Publication date
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