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WO2015101693A1 - Compositions et préparations combinées pour le traitement des douleurs oropharyngées - Google Patents

Compositions et préparations combinées pour le traitement des douleurs oropharyngées Download PDF

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Publication number
WO2015101693A1
WO2015101693A1 PCT/ES2014/071001 ES2014071001W WO2015101693A1 WO 2015101693 A1 WO2015101693 A1 WO 2015101693A1 ES 2014071001 W ES2014071001 W ES 2014071001W WO 2015101693 A1 WO2015101693 A1 WO 2015101693A1
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Prior art keywords
composition
ketamine
pain
treatment
oral
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English (en)
Spanish (es)
Inventor
Manuel CORTIÑAS SÁENZ
Inmaculada ALFÉREZ GARCÍA
Ana VEGA SALVADOR
Miren Beatriz MENOYO ALONSO
Luciano AGUILERA CELORRIO
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Servicio Andaluz de Salud
Administracion General de la Comunidad Autonoma de Euskadi
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Servicio Andaluz de Salud
Administracion General de la Comunidad Autonoma de Euskadi
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Publication of WO2015101693A1 publication Critical patent/WO2015101693A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics

Definitions

  • the present invention is within the field of Medicine and Pharmacy, and refers to a composition and / or a combined preparation comprising arylcycloalkylamines, structurally related to cyclidines, such as ethiciclidine, phencyclidine, roliciclidine and tenociclidine, and synthetic opiates. for the treatment of oral mucositis and pain associated with oral mucositis. Particularly, it refers to compositions comprising ketamine and meperidine and combined preparations of ketamine and meperidine, for the treatment of pain, particularly, for the treatment of pain associated with oral mucositis and for the treatment of oral mucositis.
  • Oral erythematous and ulcerative mucositis is an oral complication of the therapy of cancer patients, characterized by having a high prevalence, high associated comorbidity and for which there is no effective treatment.
  • Oral mucositis or stomatitis is characterized by an inflammatory reaction that affects the mucous membranes of the entire digestive tract and is one of the main adverse effects of chemotherapy, radiotherapy and bone marrow transplants.
  • mucositis encompasses all the alterations that occur on the body's mucous membranes, from the orolabial to the anogenital, as a consequence of the chemotherapy and radiotherapy treatment.
  • Oral mucositis or stomatitis occurs in a percentage that ranges between 30% and 50% of patients undergoing chemotherapy treatment and up to 90% of those receiving radiotherapy on the oral cavity, especially if the dose exceeds 4,000 -6,000 cGy. Up to 76% of bone marrow transplanted patients develop this entity. Up to 97% of patients with head and neck cancer, and 100% of those undergoing fractional radiotherapy for a long time develop this disease. In summary, up to 40% of Patients receiving chemotherapy and radiotherapy develop clinical oral mucositis.
  • the pathogenesis of oral mucositis is developed by a mechanism of direct toxicity due to a decrease in the renewal of the epithelial baseline and by indirect toxicity due to the toxic effect of chemotherapeutic agents on the bone marrow.
  • the pathophysiology of mucositis can be divided into 5 phases: an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase.
  • the onset phase occurs due to the formation of free radicals caused by chemo or radiotherapy, which damage cellular DNA. This entails the production of cellular transcription factors such as NF-kB (nuclear factor Kappa-B), which triggers an increased production of inflammatory cytokines, marking the beginning of the ulceration phase.
  • the main inflammatory cytokines involved are IL-1, IL-6 and TNF-alpha.
  • the ulcer area attracts epithelial cells that begin the process of re-epithelialization of the lesion.
  • Pain in the patient with cancer is of a high prevalence.
  • the pain is an aspect essential of the oncological disease that must be treated as such and its therapeutic approach should be considered as an important priority as the underlying disease, since pain and uncontrolled pain crises can become as devastating as the disease itself Oncological
  • Pain associated with oral mucositis has been reported as one of the worst symptoms by patients receiving chemotherapy treatment for head and neck cancer (Rose-Ped AM, Bellm LA, Epstein JB, et al. 2002. Complications of radiation therapy for head and neck cancers: The patient perspective, Cancer Nurs, 25: 468-9). Proper pain management is essential to ensure positive results for patients with mucositis. Cancer-induced mucositis causes acute pain, which is the result of epithelial detachment, inflammation of the mucosa, and ulceration (Camp-Sorrell D. 2000. Chemotherapy: toxicity management. In: Yarbro CH, Frogge MH, Goodman M, et al. (Eds.) Cancer nursing.
  • Tissue injury activates nociceptive receptors by creating pain, which resolves with damage to underlying tissues (Debra J Harris 2006. Cancer treatment-induced mucositis pain: sirategies for assessment and management. Therapeutics and Cl ⁇ nica! Risk Management, 2 (3) : 251-258).
  • analgesic treatment is based on the administration of topical morphine sulfate and topical lidocaine, supplemented with cryotherapy.
  • opioid analgesics by mouth (morphine, oxycodone, tapentadol, etc.). If it is not tolerated orally, treatment options are transdermal fentanyl or buprenorphine.
  • NSAIDs that affect platelet adhesion, alter the gastric mucosa and are potentially nephrotoxic are contraindicated.
  • the commercially available rinses can be classified as:
  • Mucosal lining rinses They usually consist of maltodextrin, polyvinylpyrrolidone and sodium hyaluronate, which create a film on the surface of the mucosa and protects it from the direct effects of food, liquids and saliva. Its analgesic effect is very moderate and of a temporary nature.
  • a first aspect of the invention relates to a composition, hereinafter composition of the invention, comprising: a) a free base or any of its pharmaceutically acceptable salts, wherein the free base has the formula (I):
  • R- it is selected from the list consisting of hydrogen, chlorine, bromine, methyl, methoxy and hydroxy, and R is an alkyl radical of one or two carbon atoms; Y b) an opioid antagonist of the peripheral mu receptors.
  • the opioid antagonist is selected from the list consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, mepehdine (pethidine), methadone, morphine , nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil or tramadol or any of its pharmaceutically acceptable salts, or any combination thereof.
  • R- it is chlorine, and R is an alkyl of a carbon atom.
  • the free base of the composition of the present invention is ketamine where said ketamine may be present in said composition in its racemic form (RS) -2- (2-chlorophenyl) -2- (methylamine) cyclohexan-1 - one or as any of its R or S isomers.
  • the opioid agonist of the peripheral mu receptors is mependin (pethidine), of formula (II):
  • the free base is ketamine and the opioid agonist of the peripheral mu receptors is mepehdine (pethidine). More preferably, the composition is a pharmaceutical composition.
  • the composition further comprises another active ingredient.
  • the present invention relates to a composition where components a) and b) are juxtaposed, in the form of a combined preparation.
  • the combined composition or preparation is a pharmaceutical composition or a combined pharmaceutical preparation.
  • a second aspect of the present invention relates to a combined preparation, hereafter combined preparation of the invention, comprising two components: a) Component A: a free base or any of its pharmaceutically acceptable salts, where the free base It has the formula (I):
  • R- it is selected from the list consisting of hydrogen, chlorine, bromine, methyl, methoxy and hydroxy, and R is an alkyl radical of one or two carbon atoms; and b) Component B: an opioid antagonist of the peripheral mu receptors.
  • the opioid antagonist is selected from the list consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, mependin (pethidine), methadone, morphine , nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil or tramadol or any of its pharmaceutically acceptable salts, or any combination thereof.
  • R- it is chlorine, and R is an alkyl of a carbon atom.
  • the free base of the combined preparation of the present invention is ketamine or (RS) -2- (2-chlorophenyl) -2- (methylamino) cyclohexan-1 -one.
  • the opioid agonist of the peripheral mu receptors is meperidine (pethidine), of formula (II):
  • the free base is ketamine and the opioid agonist of the peripheral mu receptors is meperidine (pethidine).
  • the combined preparation further comprises another active ingredient.
  • a third aspect of the invention relates to a pharmaceutical form, hereinafter pharmaceutical form of the invention, comprising the composition of the invention or components a) and / or b) of the combined preparation of the invention.
  • a fourth aspect of the invention relates to a composition
  • a composition comprising:
  • the opioid antagonist of the peripheral mu receptors meperidine (pethidine) or any of its pharmaceutically acceptable salts for topical use in the treatment of pain.
  • the composition is used topically in the treatment of oropharyngeal or orofacial algias, preferably orofacial neoplasms.
  • the composition is used topically in the oropharyngeal cavity in the treatment of oropharyngeal or orofacial algias.
  • the composition is used topically in the oropharyngeal cavity in a pharmaceutically acceptable form suitable for performing mouthwashes, in the treatment of oropharyngeal or orofacial algias.
  • the composition is used topically in the oropharyngeal cavity in the form of an oral solution, a rinse, a mouthwash and / or a pharmaceutically acceptable gargle suitable for performing mouthwashes, in the treatment of oropharyngeal algias or orofacial algias.
  • the oropharyngeal algias are selected from the list consisting of pain associated with oral mucositis induced by chemotherapy or radiotherapy, trigeminal neuralgia, glossopharyngeal neuralgia, syndrome of burning or burning mouth, pain associated with postoperative adeno-tonsillectomy and cancer pain caused by head-neck neoplasms.
  • a fifth aspect of the invention relates to the composition, the combined preparation or the pharmaceutical form of the present invention in the form of an oral solution.
  • the free base is ketamine and the opioid agonist of the peripheral mu receptors is meperidine.
  • the ketamine is in a dose of 0.5-1 mg / kg of patient.
  • the ketamine is in a concentration of 0.5 to 30 mg / mL, preferably 10 to 20 mg / mL, preferably 0.5 to 20 mg / mL, preferably 5 to 20 mg / mL, more preferably 5 to 15 mg / mL, more preferably in a concentration of 7 to 13 mg / mL, even more preferably in a concentration of 9 to 1 1 mg / mL, even more preferably in a concentration of about 10 mg / mL.
  • the oral solution comprises meperidine in a concentration of 0.1 to 20 mg / mL, such as in a concentration of 5 to 20 mg / mL, preferably in a concentration of 1 to 10 mg / mL, more preferably in a concentration of 2 to 8 mg / mL, still more preferably in a concentration of 4 to 6 mg / mL, even more preferably in a concentration of about 5 mg / mL.
  • the oral solution of the present invention comprises ketamine in a concentration of 5 to 20 mg / mL and meperidine in a concentration of 5 to 20 mg / mL.
  • the oral solution of the present invention comprises ketamine in a concentration of about 10 mg / mL and meperidine in a concentration of about 5 mg / mL.
  • the pharmaceutical form of the present invention can also be presented in the form of mouthwash, mouthwash, gargle, elixir, etc.
  • the pharmaceutical form of the present invention (for example, the oral solution of the present invention, the rinse of the present invention or the mouthwash of the present invention) is preferably formulated with a simple syrup and / or with Ora-Sweet®.
  • the pharmaceutical form of the present invention may comprise other components, additives or active ingredients.
  • the present invention relates to a pharmaceutical form comprising ketamine in a concentration of 0.5 to 30 mg / ml, 20 to 30 mg / ml (in particular approximately 25 mg / ml), of 0.5 at 20 mg / ml, 5 to 20 mg / mL, preferably 7 to 13 mg / mL and meperidine in a concentration of 0.1 to 20 mg / ml, preferably 2 to 8 mg / mL.
  • the oral solution is formulated with simple syrup and / or with Ora-Sweet®.
  • the present invention also relates to a pharmaceutical form comprising ketamine in a concentration of 9 to 1 1 mg / mL, such as about 10 mg / mL, and meperidine in a concentration of 4 to 6 mg / mL, such as approximately 5 mg / mL.
  • the oral solution is formulated with simple syrup and / or with Ora-Sweet®.
  • a preferred embodiment of the fifth aspect of the invention relates to any of the pharmaceutical forms of said aspect for any of the uses described in the fourth aspect of the invention.
  • kits for the preparation of a composition comprising:
  • R- it is selected from the list consisting of hydrogen, chlorine, bromine, methyl, methoxy and hydroxy, and R is an alkyl radical of one or two carbon atoms;
  • a package comprising an opioid antagonist of the peripheral mu receptors.
  • the opioid antagonist is selected from the list consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil or tramadol, or any of its pharmaceutically acceptable salts, or any combination thereof; and, optionally, c) a package comprising a vehicle for oral syrups, wherein said vehicle preferably comprises 70% sucrose, 6% glycerin, 5% sorbitol, less than 1% sodium saccharin, xanthan gum and aroma, 0.03 % methylparaben, 0.008% propylparaben, 0.1% potassium sorbate and purified water (csp).
  • a vehicle for oral syrups wherein said vehicle
  • components a) and b) of the sixth aspect of the invention are those described in the composition of the fourth aspect of the invention.
  • a seventh aspect of the present invention relates to the use of the composition, of the combined preparation, of the pharmaceutical form or of the kit of the present invention in the preparation of a medicament, preferably in the elaboration of a medicament for the treatment of the oral mucositis and / or for the treatment of pain associated with oral mucositis and / or for the treatment of oral lesions secondary to tumor progression and associated neuralgia symptoms.
  • a medicament for the treatment of the oral mucositis and / or for the treatment of pain associated with oral mucositis and / or for the treatment of oral lesions secondary to tumor progression and associated neuralgia symptoms.
  • the invention relates to the composition, the combined preparation, the pharmaceutical form or the kit of the present invention for use as a medicament, preferably for use in the treatment of oral mucositis and / or pain associated with mucositis.
  • Figure 1 Flow chart of patients during the follow-up period and the causes of exclusion.
  • Figure 2. Measurement of pain and episodes of breakthrough pain using an analog visual scale (VAS) based on treatment with rinses of ketamine hydrochloride (KTM) versus rinses of ketamine hydrochloride (KTM) and meperidine (KTM + MEPER) with respect to pain Baseline upon admission to the Unit.
  • VAS analog visual scale
  • Figure 3 Pain measurement by analog visual scale (VAS) as a function of treatment with rinses of ketamine hydrochloride (KTM) versus rinses of ketamine hydrochloride (KTM) and ketamine-meperidine (KTM + MEPER). * Statistically significant differences (p ⁇ 0.05).
  • FIG. 1 Pain intensity using a Visual Analog Scale (VAS), comparison between groups during the first week post-migdalectomy.
  • KTM-MEP Group Ketamine and Meperidine Group.
  • the present invention provides a composition and a combination therapy that decreases the consumption of other drug cocktails used in the treatment of pain, and which is useful in the treatment of oropharyngeal algias, such as pain associated with oral mucositis, avoiding or minimizing the side effects of other treatments.
  • the authors of the present invention describe the use of rinses of various opioid substances and NMDA receptor antagonists as a highly effective option for the treatment of rebel oropharyngeal algias compared to conventional treatments without systemic analgesic effects. In this way, the authors of the present invention describe how the dual combination of both drugs at the topical level leads to a cessation of overstimulation of NMDA receptors and opioid receptors type mu [ ⁇ ], which in turn modifies the entire cascade of events of inflammatory and hyperalgesic phenomena derived from the activation of second protein kinase type messengers, magnesium and calcium receptors.
  • the alteration of calcium levels entails in turn an activation of various protein kinases, production of nitric oxide synthetase and mitochondrial superoxide, which are partly responsible for the stimulation of the primary synthetase enzymes in the phenomena of mitochondrial respiration and cellular apoptosis. . Therefore, its use entails both an improvement in pain states and a decrease in the duration of the pictures of various oropharyngeal algias, such as oral mucositis.
  • a first aspect relates to a composition, hereafter referred to as the invention, which comprises: a) a base or any of its salts, esters, ethers, solvates, stereoisomers, tautomers, and pharmaceutically prodrugs, derivatives or analogs acceptable, where the free base has the formula (I)
  • R- it is selected from the list consisting of hydrogen, chlorine, bromine, methyl, methoxy and hydroxy, and R is an alkyl radical of one or two carbon atoms, and b) an opioid antagonist of the peripheral mu [ ⁇ ] receptors, or any of its pharmaceutically acceptable salts.
  • the free base as component a) of the composition of the present invention is ketamine, of the name IUPAC 2- (2- chlorophenyl) -2- (methylamine) cyclohexan-1 -one, CAS number 6740-88-1, and formula (III):
  • the free base is ketamine hydrochloride.
  • Ketamine a dissociative drug with hallucinogenic potential, derived from phencyclidine, originally used in medicine for its analgesic and, above all, anesthetic properties. Pharmacologically, it is classified as an NMDA receptor antagonist. It also interacts with muscarinic receptors, monoaminergic descending algic cascades and dependent voltage calcium channels.
  • NMDA or NMDAr receptors are ionotropic glutamate receptors, a neurotransmitter, which act as priority components in neuronal plasticity and memory.
  • the NMDA receptor belongs to a family of ionotropic receptors of the glutamate activating amino acid and is characterized by high affinity for glutamate, high unit conductance, high calcium permeability and a voltage-dependent blockade by magnesium ions (Zito K and Scheuss V. (2009) NMDA Receptor Function and Physiological Modulation. ln: Encyclopedia of Neuroscience (Squire LR, ed), volume 6, pp. 1 157-1 164. Oxford: Academic Press).
  • Ketamine is used in medicine as an anesthetic, usually as an intravenous or intramuscular injection.
  • the dissociative anesthetic effects of ketamine have also been applied for the treatment of postoperative pain.
  • the peripheral ⁇ [mu] receptor opioid agonist is selected from the list consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocin, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine ), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil or tramadol, or any of its pharmaceutically acceptable salts, or any combination thereof.
  • component b) of the composition of the present invention is an opioid agonist of one or more opioid receptors.
  • it is an opioid agonist of the mu and kappa receptors.
  • it is an opioid agonist of the mu, delta and kappa receptors.
  • component b) of the composition of the present invention is also an opioid agonist of the kappa receptors.
  • the kappa opioid is one of five related receptors that bind opium-like components in the brain and are responsible for mediating the effects of those components. These effects include alterations in pain perception, awareness, motor control and mood.
  • Opioid agonists of the present invention include, but are not limited to dipipanone, heroin, tramadol, ethephine, dihydroetorphine, butorphanol, levorphanol, alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanyl derivatives of its pharmaceutically acceptable salts or mixtures thereof.
  • the opioid agonist of the composition of the invention is meperedin, derivatives thereof or salts thereof.
  • All compounds of the present invention include pharmaceutically acceptable salts, esters, amides and prodrugs, including but not limited to carboxylic salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention that are, within the scope of medical judgment, suitable for use in patients without excessive toxicity, irritation, allergic response, and the like, with a reasonable benefit / risk ratio, and effective for its intended use, as well as hybrid ion forms (zwitterionic forms, in English), where possible, of the compounds of the present invention.
  • salts refers to the relatively harmless, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by reacting separately the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • salts include the salts hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobsonate, lauryl sulphonate, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and ammonium such as, as well as harmless ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium , methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like (see for example, Berge SM, et al, "Pharmaceutical Salts," J.Pharm.Sci., 1977; 66: 1-19, the content of which is incorporated in this application by reference).
  • prodrug refers to compounds that are rapidly transformed in vivo to produce the parent compound of the above formulas, for example, by hydrolysis in the blood.
  • prodrugs are provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference.
  • Opioids exert their action through binding to specific receptors that are widely distributed in the CNS, as well as in the digestive system, cardiovascular, endocrine system, etc.
  • Five different types of opioid receptors have been described: mu, kappa, delta, sigma and epsilon; each with different effects and locations.
  • Known opioid receptors are part of the family of G protein-associated receptors (Howard Fields, 2004, Nature Reviews, Neuroscience, 5: 565-575).
  • the opioid agonist comprising the composition of the present invention is the meperidine or pethidine of formula (II):
  • Meperidine acts as an agonist on the mu [ ⁇ ], delta and especially kappa receptors, in addition to having local anesthetic properties. This drug is ten times less potent than morphine, but it is somewhat more fat-soluble, and its onset of action it is faster. It is well absorbed by all routes, with an oral bioavailability around 50%.
  • the invention provides a composition comprising ketamine and mepehdine, or any of its pharmacologically acceptable salts.
  • the composition or the combined preparation of the present invention is a pharmaceutical composition.
  • the composition further comprises another active ingredient.
  • Another aspect of the invention relates to a combined preparation comprising: a) a free base or any of its pharmaceutically acceptable salts, wherein the free base has the formula (I)
  • R- it is selected from the list consisting of hydrogen, chlorine, bromine, methyl, methoxy and hydroxy, and R is an alkyl radical of one or two carbon atoms, and b) an opioid antagonist of the peripheral mu receptors, or any of their salts pharmaceutically acceptable.
  • R- it is chlorine, and R is an alkyl of a carbon atom.
  • the free base is 2- (2-chlorophenyl) -2- (methylamine) cyclohexan-1 -one, also called ketamine or any of its salts, esters, ethers, solvates, stereoisomers, tautomers, prodrugs, derivatives or the like, or any combination thereof.
  • the present invention includes both the racemic form of ketamine and any of its isomers, in particular the present invention includes the S - (+) Ketamine isomer.
  • the opioid antagonist of the peripheral mu receptors is selected from the list consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil or tramadol, or any of its pharmaceutically acceptable salts, or any combination thereof.
  • the synthetic opioid is meperidine or pethidine, or any of its pharmaceutically acceptable salts.
  • the combined preparation of the invention comprises ketamine and meperidine, and / or any of its pharmaceutically acceptable salts.
  • the term “combined preparation” or also called “juxtaposition”, herein, means that the components of the combined preparation need not be present as a joint, for example in a true composition, in order to be available for combined application. , separate or sequential. In this way, the expression “juxtaposed” implies that it is not necessarily a true combination, in view of the physical separation of the components.
  • Another aspect of the invention relates to a pharmaceutical form, hereinafter pharmaceutical form of the invention, comprising the composition of the invention, the combined preparation of the invention, any of the components a) or b) of the combined preparation of the invention, or simultaneously, components a) and b) of the combined preparation of the invention.
  • the pharmaceutical form is the individualized arrangement to which drugs (active ingredients) and excipients (pharmacologically inactive matter) are adapted to constitute a medicament.
  • liquid pharmaceutical forms can be solutions (oral solutions), aromatic waters, syrups, elixirs, mouthwashes, mouthwashes, potions, mucilages, emulsions, suspensions, hills, lotions, tinctures, fluid extracts, injections, gargles, etc.
  • compositions comprising one or more compounds of the invention described above together with a pharmaceutically acceptable carrier.
  • the compounds are normally combined with one or more adjuvants appropriate for the indicated route of administration.
  • the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate , polyvinylpyrrolidone, and / or polyvinyl alcohol.
  • the compounds of this invention can be dissolved in saline, water, polyethylene glycol, propylene glycol, colloidal solutions of carboxymethyl cells, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and / or various buffers.
  • Other adjuvants and modes of administration are well known in the pharmaceutical art.
  • the carrier or diluent may include temporary delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the pharmaceutical form of the invention comprises ketamine and meperidine, and / or any of its pharmaceutically acceptable salts.
  • the pharmaceutical composition or any of the components a) or b) of the combined preparation of the invention, or both is formulated as an oral solution.
  • the pharmaceutical composition or any of the components a) or b) of the combined preparation of the invention, or both is formulated as a rinse.
  • the pharmaceutical composition or any of the components a) or b) of the combined preparation of the invention, or both is formulated as a mouthwash.
  • the pharmaceutical composition or any of the components a) or b) of the combined preparation of the invention, or both is formulated as a gargle.
  • a rinse is understood as a liquid that serves to rinse, that is, to clean the mouth and dentures.
  • a mouthwash is understood as a medicinal rinse.
  • a gargle is understood as a liquid that serves to gargle, that is, to keep the liquid in the throat, with the mouth facing up, without swallowing it and expelling the air, which produces a similar noise. to boiling water.
  • the oral solution of the invention, the rinse, the mouthwash and / or the gargle of the invention comprises keratin and meperidine, and / or any of its pharmaceutically acceptable salts.
  • Another aspect of the invention relates to a pharmaceutical form such as an oral solution, a rinse, a mouthwash and / or a gargle comprising ketamine in a dose of 0.3 to 1 mg / kg of the patient, and preferably, of 0.5 to 0.7 mg / kg of the patient and more preferably 0.6 mg / kg of the patient.
  • a pharmaceutical form such as an oral solution, a rinse, a mouthwash and / or a gargle comprising ketamine in a dose of 0.3 to 1 mg / kg of the patient, and preferably, of 0.5 to 0.7 mg / kg of the patient and more preferably 0.6 mg / kg of the patient.
  • the pharmaceutical form of the invention comprises ketamine in a concentration of 0.5 to 30 mg / ml_, such as for example approximately 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 10, 1 1, 12, 13, 14, 15, 20, 22, 25, 27 and 30 mg / ml_.
  • the pharmaceutical form of the invention comprises ketamine in a concentration of 5 to 30 mg / ml_, preferably 20 to 30 mg / ml, preferably 5 to 20 mg / ml, preferably 5 to 15 mg / ml_, more preferably 7 to 13 mg / ml_, still more preferably 9 to 1 1 mg / ml_.
  • the pharmaceutical form of the invention comprises ketamine in a concentration of approximately 10 mg / ml_. It is noted that the concentration of ketamine will depend on the type of ailment to be treated (see the different concentrations of the Ketamine-Meperidine combination used in the examples of the present invention).
  • the pharmaceutical form of the present invention such as an oral solution, a rinse, a mouthwash and / or a gargle is preferably formulated with a standard carrier such as a simple syrup.
  • a standard carrier such as a simple syrup.
  • a simple syrup in the context of the present invention is understood as an aqueous preparation for oral use characterized by a sweet taste and viscous consistency. It may contain sucrose at a concentration of at least 45% m / m. Its sweet taste can also be obtained using other polyols or sweetening agents. Syrups normally contain other flavoring or flavoring agents.
  • Each dose of a multidose container is administered by means of an appropriate device that allows to measure the prescribed volume.
  • Ora-Sweet® is a vehicle for oral syrups, free of glucose and alcohol, especially suitable for pediatric and geriatric preparations.
  • a small amount of sodium saccharin gives it sweetness.
  • Xanthan gum, glycerin and sorbitol contribute to both texture and good flow characteristics. Contains flavoring agents to increase palatability. It is stored at a slightly acidic pH to help decrease the degradation of the active substances through oxidation.
  • composition of this vehicle for oral syrups comprises:
  • -Other ingredients present in amounts less than 1% and considered and generally recognized as safe for oral consumption (sodium saccharin, xanthan gum and aroma. It is buffered with citric acid and sodium citrate. It also has methylparaben (0.03%), propylparaben ( 0.008%), and potassium sorbate (0.1%)).
  • the pharmaceutical form such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention may comprise other additives such as preservatives, aromas, sweeteners, thickeners, etc.
  • this aspect of the invention relates to a pharmaceutical form such as an oral solution, a rinse, a mouthwash and / or a gargle, comprising simple syrup and / or Ora-Sweet®, and ketamine in a concentration between 0.5 to 30 mg / mL, such as about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 10, 1 1, 12, 13, 14, 15, 20, 22, 27 and 30 mg / mL
  • the pharmaceutical form of the invention comprises ketamine in a concentration of 5 to 30 mg / mL, preferably 20 to 30 mg / ml, preferably 5 to 20 mg / ml, preferably from 5 to 15 mg / mL, more preferably from 7 to 13 mg / mL, still more preferably from 9 to 1 1 mg / mL.
  • the pharmaceutical form of The invention comprises ketamine in a concentration of approximately 10 mg / mL.
  • -Other ingredients present in amounts less than 1% and considered and generally recognized as safe for oral consumption (sacanna sodium, xanthan gum and aroma. It is buffered with citric acid and sodium citrate. It also has methylparaben (0.03%), propylparaben ( 0.008%), and potassium sorbate (0.1%))
  • the pharmaceutical form such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention further comprises mepehdine in a final concentration of 0.1 to 20 mg / mL, as for example about 0, 1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 17, 18, 19, 20 mg / mL, or as for example in a final concentration of 5 to 20 mg / mL.
  • the pharmaceutical form such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention further comprises mepehdine in a final concentration of 1 to 10 mg / mL, more preferably 2 to 8 mg / mL , even more preferably from 4 to 6, even more preferably in a final concentration of about 5 mg / mL.
  • ketamine in a concentration of approximately 10 mg / mL
  • meperidine in a concentration of approximately 5 mg / mL
  • simple syrup and / or Ora-Sweet® optionally, in a final volume of approximately 100 mL.
  • kits-of-parts of the English “kit of parts" for the preparation of the composition or of the combined preparation or of the pharmaceutical form of the invention.
  • kit refers to a combination of a set of components suitable for obtaining the composition or the combined preparation or the pharmaceutical form of the invention, which may or may not be packaged together, along with their appropriate containers and containers for commercial sale, etc.
  • suitable component for obtaining the composition or the combined preparation or the pharmaceutical form of the invention any compound that can be used for obtaining them, and includes, without limitation , aqueous solutions, solid preparations, buffers, syrups, preservation solutions, flavorings, pH correctors, thickeners, etc.
  • kit components can be provided in separate vials (in the form of "part-kit") or in a single vial.
  • the kit of the present invention is intended for the preparation of the composition or of the combined preparation or of the pharmaceutical form (for example, of the oral solution, mouthwash, rinse, gargle, elixir, etc.) of the invention.
  • the kit components of the present invention are ready to be used to prepare the combined composition or preparation or the pharmaceutical form of the present invention.
  • the kit preferably contains explanatory instructions on how to prepare the combined composition or preparation or the pharmaceutical form of the present invention. Instructions can be provided to users electronically or on paper.
  • the invention provides a kit for the preparation of a composition, or of a combined preparation, or of a pharmaceutical form comprising a container comprising:
  • R- it is selected from the list consisting of hydrogen, chlorine, bromine, methyl, methoxy and hydroxy, and R is an alkyl radical of one or two carbon atoms; b) a container with an opioid antagonist of the peripheral mu receptors;
  • the opioid antagonist is selected from the list consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, pentazocine propiram, propoxyphene, sufentanil or tramadol, or any of its pharmaceutically acceptable salts, or any combination thereof; and, optionally, c) a container with a vehicle for oral syrups that optionally comprises 70% sucrose, 6% glycerin, 5% sorbitol, less than 1% sodium saccharin, xanthan gum and aroma, 0.03% methylparaben, 0.008% propylparaben, 0.1% potassium sorbate and purified water (csp).
  • a vehicle for oral syrups that optionally comprises 70% sucrose, 6% glycerin,
  • Component (c) can also be a simple syrup container.
  • the kit of the invention comprises a container comprising a container with ketamine, a container with meperidine and, optionally, a container with a vehicle for oral syrups comprising simple syrup, Ora-Sweet® or a vehicle for oral syrups comprising 70% sucrose, 6% glycerin, 5% sorbitol, less than 1% sodium saccharin, xanthan gum and aroma, 0.03% methylparaben, 0.008% propylparaben, 0.1% potassium sorbate and purified water ( csp).
  • a container comprising a container with ketamine, a container with meperidine and, optionally, a container with a vehicle for oral syrups comprising simple syrup, Ora-Sweet® or a vehicle for oral syrups comprising 70% sucrose, 6% glycerin, 5% sorbitol, less than 1% sodium saccharin, xanthan gum and aroma, 0.03% methylparaben, 0.008% propylparaben,
  • ketamine hydrochloride rinses associated with meperidine entail excellent analgesia in the case of oral mucositis secondary to chemotherapy and radiotherapy, with a control of the pain that we describe as excellent. Moreover, this excellent pain control also occurs in other cases as the authors of the present invention have proven, among which we stand out for the number of patients treated by pathology such as:
  • the examples of the present invention describe the use of ketamine hydrochloride rinses associated with meperidine for each of these indications with excellent results.
  • the adverse effects have been minor and of a very temporary nature.
  • liver and kidney function controls have been performed in patients with prolonged treatment with ketamine hydrochloride rinses associated with meperidine without observing notable analytical alterations.
  • This dual combination of drugs at the topical level entails a cessation of the overstimulation of NMDA receptors and of the opioid receptors type ⁇ , which in turn modifies the entire cascade of events of inflammatory and hyperalgesic phenomena derived from the activation of second protein messenger type messengers. , magnesium and calcium receptors.
  • the alteration of calcium levels in turn leads to an activation of various protein kinases, oxide production Nitric synthetase and mitochondrial superoxide, which are partly responsible for the stimulation of the primary synthetase enzymes in the phenomena of mitochondrial respiration and cellular apoptosis.
  • the examples of the present invention demonstrate that the composition of the invention used topically in the form of gargles causes a decrease in the duration of the process of different oropharyngeal algias, as well as a marked reduction in pain in patients.
  • This aspect is of the utmost importance, since in the case of oral mucositis, its mucositis appearance leads to a delay in the administration of the following chemotherapy cycles.
  • the duration of the clinical picture of mucositis is reduced, as well as the pain associated therewith.
  • the combination therapy (composition of the invention) of the present invention yields more positive results than treatment with a single active ingredient (e.g. ketamine) as demonstrated by example 7 of the present invention. Therefore, the effect of two components of the composition of the invention is highly beneficial and unexpected.
  • another aspect of the invention relates to the use of the composition and / or the combined preparation; and / or in the pharmaceutical form; and / or of the kit of the invention in the preparation of a medicament, or alternatively, to the composition, and / or to the combined preparation, and / or to the pharmaceutical form, and / or to the kit of the invention, for use as a medicament .
  • Another aspect of the invention relates to the use of the composition, of the combined preparation, of the pharmaceutical form, and / or of the kit of the invention in the preparation of a medicament for the treatment of pain, or alternatively, to the composition, to the combined preparation, to the pharmaceutical form and / or to the kit of the invention, for use in the treatment of pain.
  • the algias are preferably selected from the list consisting of pain associated with oral mucositis induced by chemotherapy or radiotherapy, trigeminal neuralgia, glossopharyngeal neuralgia, syndrome burning or burning mouth, pain associated with postoperative adeno-tonsillectomy and cancer pain caused by head-neck neoplasms.
  • Another aspect of the invention relates to a composition comprising: a.
  • the opioid antagonist of the peripheral mu receptors meperidine (pethidine) or any of its pharmaceutically acceptable salts for topical use in the treatment of pain.
  • pethidine peripheral mu receptors meperidine
  • the opioid antagonist of the peripheral mu receptors meperidine (pethidine) or any of its pharmaceutically acceptable salts for topical use in the treatment of pain.
  • pethidine peripheral mu receptors meperidine
  • the opioid antagonist of the peripheral mu receptors meperidine (pethidine) or any of its pharmaceutically acceptable salts for topical use in the treatment of pain.
  • pethidine meperidine
  • any of its pharmaceutically acceptable salts for topical use in the treatment of pain.
  • oropharyngeal algias Preferably for topical use in the treatment of oropharyngeal algias. More preferably, for use topically in the oropharyngeal cavity in the treatment of oropharyngeal algias. More preferably, for use topically in the oropharyngeal cavity in a pharmaceutical
  • a rinse, a mouthwash and / or a pharmaceutically acceptable gargle suitable for performing mouthwashes in the treatment of oropharyngeal algias More preferably, for use topically in the oropharyngeal cavity in any of the pharmaceutical forms described in the present invention in the treatment of algal orophalanges.
  • topical route means the route of administration of drugs used by the skin and mucous membranes.
  • this includes the conjunctival, oral and urogenital mucosa.
  • this pathway includes the mucosa of the oropharyngeal cavity.
  • algia is understood as synonymous with pain. However, it is applied more to a special form of paroxysmal pain and with a tendency to repeat itself that is accompanied by fear or anxiety in the event of a recurrence called neuralgia (eg Trigeminal Neuralgia).
  • neuralgia eg Trigeminal Neuralgia
  • oropharyngeal algias is understood as the painful sensation from the eustachian tube to the upper part of the hypopharynx.
  • Oropharyngeal algias are preferably selected from the list consisting of pain associated with oral mucositis induced by chemotherapy or radiotherapy, trigeminal neuralgia, glossopharyngeal neuralgia, burning or burning mouth syndrome, pain associated with Postoperative adeno-tonsillectomy and cancer pain caused by head-neck neoplasms.
  • compositions for the use indicated in the preceding paragraphs may be in the form of a combined preparation comprising components a) and b), where said components a) and b) are juxtaposed.
  • compound 2- (2-chlorophenyl) -2- (methylamino) cyclohexan-1 -one can be found in its racemic form (RS) -2- (2- chlorophenyl) -2- (methylamine) ) cyclohexan-1 -one or as the S - (+) 2- (2-chlorophenyl) -2- (methylamino) cyclohexan-1 -one isomer or as the R - (-) 2- (2-chlorophenyl) isomer - 2- (methylamine) cyclohexan-1 -one or as any combination thereof.
  • pain intensity scales such as: one-dimensional scales, which include the numerical rating scale (for example, from 0 to 10), a scale with verbal description (for example, "no pain,” “ mild pain, “” moderate pain, “” intense pain ") or similar visual scales (VAS) (for example, a 10 cm line with captions such as” no pain "on the left end and” severe pain "on the right end; the patient indicates the place of the line that best represents intensity of pain).
  • VAS visual scales
  • a series of scales that use face drawings (from smiling faces to distressed faces) for patients who cannot easily use the tools mentioned above.
  • treatment with the composition, with the combined preparation, with the pharmaceutical form and / or with the kit of the invention is carried out in human patients with chronic pain, preferably with chronic orofacial oncological pain (preferably with a score on an analog visual scale greater than 7), ideally in patients who show resistance to usual opioid treatment, preferably in patients with entematosus and ulcerative oral mucositis, preferably in patients with chemotherapy or radiotherapy-induced oral mucositis grade III or IV.
  • the term "resistance to usual opioid treatment” is understood as a treatment in which the opioid intake was at least 60 mg of oral morphine per day, 25 mg of transdermal fentanyl every hour, 30 mg of oxycodine per day, 200 mg of tapentadol per day or an equianalgesic dose of another opioid for a week or more.
  • the treatment with the composition, with the combined preparation, with the pharmaceutical form and / or with the kit of the invention is carried out in the form of daily mouthwashes, for example at least one daily mouthwash, or two, or three, or more daily mouthwashes, 3-15 mL each rinse, preferably 4-10 mL, even more preferably 4-5 mL for at least 45 consecutive days, preferably at least 30 consecutive days, more preferably at least minus 21 consecutive days, even more preferably of at least 15 consecutive days, still more preferably of at least 7 consecutive days, still more preferably of at least 3 consecutive days.
  • daily mouthwashes for example at least one daily mouthwash, or two, or three, or more daily mouthwashes, 3-15 mL each rinse, preferably 4-10 mL, even more preferably 4-5 mL for at least 45 consecutive days, preferably at least 30 consecutive days, more preferably at least minus 21 consecutive days, even more preferably of at least 15 consecutive days, still more preferably of at least 7 consecutive days, still more preferably of at
  • the treatment with the composition, with the combined preparation, with the pharmaceutical form and / or with the kit of the invention is carried out in the form of daily mouthwashes of 4-5 mL during At least three consecutive days.
  • the number of daily mouthwashes varies depending on the patient and the degree of mucositis.
  • the number of daily mouthwashes is one rinse every 4-12 hours, such as a rinse every approximately 4 hours, or a rinse every approximately 5 hours, or a rinse every approximately 6 hours, or a rinse every approximately 7 hours, or a rinse every approximately 8 hours, or a rinse every approximately 9 hours, or a rinse every approximately 10 hours, or a rinse every approximately 1 1 hours, or a rinse every approximately 12 hours, more preferably a rinse every 8 hours .
  • a rinse may be performed, or two, or three, or four, or five, or six or more daily rinses.
  • at least one daily mouthwash is performed.
  • the rinses may be of variable volume, such as about 3-15 ml_ for each rinse, preferably 4-10 ml_, even more preferably 4-5 mL for at least 45 consecutive days, and / or at least 30 consecutive days, and / or at least 21 consecutive days, and / or at least 15 consecutive days.
  • the duration of treatment is variable depending on the clinical course. Preferably, the duration of treatment is determined based on the etiology of the condition, and thus in oral mucositis post-chemotherapy has a course 15-21 days while in mucositis caused by radiotherapy is usually 30-45 days.
  • the duration of treatment is preferably 30 to 45 days.
  • the duration of treatment is preferably 15 to 21 days.
  • the duration of the treatment may be at least 45 consecutive days, preferably at least 30 consecutive days, more preferably at least 21 consecutive days, even more preferably at least 15 consecutive days, even more preferably at least 7 consecutive days, still more preferably of at least 3 consecutive days.
  • the pharmaceutical form of the present invention (such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention), which comprises ketamine in a concentration of approximately 10 mg / mL, mepehdine in a concentration of approximately 5 mg / mL and simple syrup and / or Ora-Sweet®, optionally in a final volume of 100 mL, is used in the treatment of oral mucositis or pain associated with it of daily mouthwashes, for example at least one daily mouthwash, preferably a rinse every 8 hours, of about 3-15 mL each rinse, preferably about 4-10 mL, even more preferably about 4-5 mL for at least 45 consecutive days, preferably of at least 30 consecutive days, more preferably of at least 21 consecutive days, even more preferably of at least 15 consecutive days, still more preferably of at least 7 consecutive days, still more preferably of at least 3 consecutive days.
  • ketamine in a concentration of approximately 10 mg / mL
  • the pharmaceutical form of the invention (such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention), which comprises ketamine in a concentration between 0.5 and 20 mg / mL , preferably 5 to 20 mg / mL, preferably 5 to 15 mg / mL, more preferably in a concentration of 7 to 13 mg / mL, still more preferably 9 to 1 1 mg / mL, and even more preferably in a final concentration of about 10 mg / mL, and mepehdine at a concentration of 0.1 to 20 mg / mL, such as 5 to 20 mg / mL, preferably 1 to 10 mg / mL, more preferably at a concentration of 2 to 8 mg / mL, even more preferably 4 to 6 mg / mL, and even more preferably in a final concentration of about 5 mg / mL in simple syrup with preservative and / or Ora-Sweet®, optional
  • the pharmaceutical form of the present invention (such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention), comprising ketamine in a concentration of approximately 10 mg / mL, mepehdine in a concentration of approximately 5 mg / mL and simple syrup and / or Ora-Sweet®, optionally in a final volume of approximately 100 mL, is used in the treatment of oral mucositis or associated pain.
  • the treatment comprises performing daily mouthwashes, preferably at least one daily mouthwash, more preferably one every 4-12 hours, even more preferably one every 8 hours, with approximately 4-5 mL of the pharmaceutical form of the invention during the minus 45 consecutive days, preferably of at least 30 consecutive days, more preferably of at least 21 consecutive days, even more preferably of at least 15 consecutive days, still more preferably of at least 7 consecutive days, still more preferably of at least 3 consecutive days .
  • the pharmaceutical form of the invention (such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention), which comprises ketamine in a concentration between 0.5 and 20 mg / ml_ , preferably 5 to 20 mg / ml_, preferably 5 to 15 mg / ml_, more preferably in a concentration of 7 to 13 mg / ml_, still more preferably 9 to 1 1 mg / ml_, and even more preferably in a final concentration of about 10 mg / ml_, and mepehdine in a concentration of 0.1 to 20 mg / ml_, such as 5 to 20 mg / ml_, preferably 1 to 10 mg / ml_, more preferably in a concentration of 2 to 8 mg / ml_, still more preferably 4 to 6 mg / ml_, and even more preferably in a final concentration of approximately 5 mg / ml_ in simple syrup with preservative and
  • the pharmaceutical form of the present invention (such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention), which comprises ketamine in a concentration of approximately 10 mg / ml_, mepehdine in a concentration of approximately 5 mg / ml_ and simple syrup and / or Ora-Sweet®, optionally in a final volume of approximately 100 mL, is used in the treatment of oral mucositis induced by chemotherapy or radiotherapy grade III or IV and / or the pain associated with it.
  • the treatment comprises performing daily mouthwashes, preferably at least one daily mouthwash, more preferably one every 4-12 hours, even more preferably one every 8 hours, with 4-5 mL of the pharmaceutical form of the invention for at least 45 consecutive days, preferably of at least 30 consecutive days, more preferably of at least 21 consecutive days, even more preferably of at least 15 consecutive days, still more preferably of at least 7 consecutive days, still more preferably of at least 3 days consecutive
  • the pharmaceutical form of the invention (such as an oral solution, a rinse, a mouthwash and / or a gargle of the present invention), comprising ketamine in a concentration of between 0.5 and 20 mg / ml_, preferably 5 to 20 mg / ml_, preferably 5 to 15 mg / ml_, more preferably in a concentration of 7 to 13 mg / ml_, still more preferably 9 to 1 1 mg / ml_, and even more preferably in a final concentration of about 10 mg / ml_, and meperidine in a concentration of 0.1 to 20 mg / ml_, such as 5 to 20 mg / ml_ , preferably 1 to 10 mg / ml_, more preferably in a concentration of 2 to 8 mg / ml_, still more preferably 4 to 6 mg / ml_, and even more preferably in a final concentration of approximately 5 mg / ml_ in syrup Simple with preservative and /
  • active substance means any component that potentially provides a pharmacological activity or other different effect on the diagnosis, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals.
  • the term includes those components that promote a chemical change in the preparation of the drug and are present therein in a modified form intended to provide the specific activity or effect.
  • compositions of the present invention can be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of forms known in the state. of technique
  • they can be, without limitation, in sterile aqueous solution or in biological fluids, such as serum.
  • Aqueous solutions may be buffered or unbuffered and have additional active or inactive components. Additional components include salts to modulate ionic strength, preservatives including, but not limited to, antimicrobial agents, antioxidants, chelators, and the like, and nutrients including glucose, dextrose, vitamins and minerals.
  • the compositions can be prepared for administration in solid form.
  • compositions can be combined with vague inert vehicles or excipients, including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate.
  • vague inert vehicles or excipients including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate.
  • compositions or preparations and / or their formulations can be administered to an animal, including a mammal and, therefore, to man, orally.
  • the dosage to obtain a therapeutically effective amount depends on a variety of factors, such as the age, weight, sex, tolerance, ... of the mammal.
  • the term "therapeutically effective amount” refers to the amount that comprises ketamine and mepehdine, prodrugs, derivatives or analogs of ketamine and mepehdine that produce the desired effect and, in general, will be determined , among other causes, due to the characteristics of said prodrugs, derivatives or analogues and the therapeutic effect to be achieved.
  • the "adjuvants” and “pharmaceutically acceptable carriers” that can be used in said compositions are the vehicles known to those skilled in the art.
  • Example 1 Use of simple rinses (with a single component) in the treatment of oral mucositis induced by chemotherapy or radiotherapy
  • Placebo Group 15 2 13% 0 0% - 13%
  • Success Number of cases with pain reduction greater than 33%. Effective: Both percent improvement of oral mucositis. EA: Adverse effects. EA%: Both percent of adverse effects. Satisfac: Degree of satisfaction of a numerical scale from 0 to 100, where 0 would be zero of degree of satisfaction and 100 the highest degree of satisfaction).
  • ketamine 1000 mg + 100 ml_ simple syrup with preservative or 100 ml_ Ora-Sweet® (final concentration of ketamine 10 mg / ml_) is used.
  • a syrup is an aqueous preparation for oral use characterized by a sweet taste and viscous consistency. It may contain sucrose at a concentration of at least 45% m / m. Its sweet taste can also be obtained using other polyols or sweetening agents. Syrups normally contain other flavoring or flavoring agents.
  • Each dose of a multidose container is administered by means of an appropriate device that allows to measure the prescribed volume.
  • Conditioning Proceed to the conditioning of the syrup, according to the particular specifications of each formulation.
  • the type of packaging used must be adequate and compatible with the syrup it contains.
  • Vehicle for oral syrups free of glucose and alcohol, especially suitable for pediatric and geriatric preparations.
  • a small amount of sacanna sodium gives it sweetness.
  • Xanthan gum, glyce na and sorbitol contribute to both texture and good flow characteristics.
  • -Other ingredients present in amounts less than 1% and considered and generally recognized as safe for oral consumption (sodium saccharin, gum Xanthan and aroma. It is buffered with citric acid and sodium citrate. It also has methylparaben (0.03%), propylparaben (0.008%), and potassium sorbate (0.1%).
  • Example 3 Use of combined rinses (Ketamine and meperidine) in the treatment of oral mucositis induced by chemotherapy or radiotherapy
  • a prospective, descriptive and non-randomized study was conducted in the Chronic Pain Unit of the Torrecárdenas Hospital in Almeria during the years 2010-2012. Inclusion criteria were those patients of legal age with a histologically confirmed cancer diagnosis and with pictures of pain attributable to mucositis, in patients receiving non-effective maintenance treatment with opiates for chronic cancer pain.
  • a maintenance treatment was considered as one in which the opioid intake was at least 60 mg of oral morphine per day, 25 micrograms of transdermal fentanyl every hour, 30 mg of oxycodone per day, 200 mg of tapentadol per day or one dose Equianalgesic of another opiode for a week or more.
  • a treatment was started with 4 ml_ of rinses of ketamine (10 mg / ml_) and meperidine (5 mg / ml_) for 4-5 minutes, being assessed in this first dose the degree of pain relief and the number and degree of occurrence of secondary diseases.
  • the patient's family was offered 5-6 syringes of the product to perform instillations every 8 hours at home. At 72 hours the patients were reassessed.
  • home treatment was prescribed with the formulation prepared by the Hospital Pharmacy Service and the Chronic Pain Unit of the Torrecárdenas Hospital of Almeria.
  • Treatment success was defined as pain relief greater than 75% of baseline VAS.
  • Partial analgesic control was defined as a decrease in baseline pain by 25-75%.
  • a progressive decrease in the Opioid base and at the time of dose stabilization a conversion of the different opiates used to equianalgesic doses of morphine was performed to evaluate the decrease in opioid consumption.
  • the degree of satisfaction of the administration of the treatment was evaluated.
  • a telephone interview and / or medical history review was carried out to evaluate the evolution weekly until resolution of the picture.
  • N Case number.
  • RDT Radiation therapy treatment.
  • QMT Chemotherapy treatment.
  • Mucositis grade Classification of mucositis grade.
  • VAS Basal pain measurement using a Visual Analog Scale (VAS). Due to the design of the study, pain using an analog visual scale was of high intensity, with values of 8.25 ⁇ 1.29.
  • the consumption of basic opioid analgesics at the beginning of treatment with rinses of ketamine and / or ketamine and meperidine was 241 ⁇ 54 mg of oral morphine, which was reduced to 133 ⁇ 39 mg of oral morphine (p ⁇ 0.001). The decrease in opioid consumption was estimated at 45%.
  • the success rate of the use of ketamine rinses was 44%.
  • the association ketamine and meperidine obtained a 100% success rate. With both treatments, the effect onset time was less than 10 minutes.
  • the main cause of failure of the ketamine rinse was the appearance of episodes of breakthrough pain.
  • Figure 2 shows the variations of pain over 24 hours and the average pain prior to the start of analgesic treatment, and on the first day after starting the rinses of ketamine (KTM) or ketamine and meperidine (KET + MEPER) .
  • Figure 3 shows the mean variation with standard deviation of the treatment with ketamine rinses with respect to the association of ketamine and meperidine rinses in cases of predictable DIO (p ⁇ 0.001).
  • Example 4 Use of combined rinses (Ketamine and meperidine) in the treatment of burning or burning mouth syndrome (SBA).
  • Burning or burning mouth syndrome is a frequent clinical picture, with a frequency in the general population estimated at 0.7 - 4.5%. It is more frequent in women, with an approximate ratio of 3: 1 to 9: 1, the most frequently affected women are in the perimenopausal period. This entity is characterized by an abnormal spontaneous sensation described by the patient as burning, burning, stinging, which affects the oral mucosa, usually in the absence of clinical and laboratory data that justify these symptoms. The area of greatest involvement is the tongue, which is why it has been called "glosslossy" and / or "glossopirosis.”
  • SBA SBA
  • oral sensory disease which includes this entity along with other idiopathic sensory disorders such as dysgeusia and xerostomia. It is usually associated with psychic disorders and has been classically included in the chapter of psychodermatosis.
  • the Lamey and Lewis classification define 3 types of SBA based on the diurnal fluctuations of symptoms.
  • Example 5 Use of combined rinses (Ketamine and meperidine) in the treatment of post-tonsillectomy pain. MATERIAL AND METHODS.
  • the inclusion criteria were those patients programmed by the Otolaryngology Service of the Torrecárdenas hospital for tonsillectomy surgery with low associated medical comorbidity (ASA 1-2), older than 16 years and who agreed to participate in the study.
  • the exclusion criteria were non-collaborating patients for any cause, age under 16 years, history of allergy to any drug in the study, possible difficulty of orotracheal intubation after airway assessment (Mallampati 3-4), known allergies to any drug of the study and the absence of informed consent.
  • the first rescue analgesic medication dexketoprofen 50 mg with a maximum dose of 150 mg / day, and as a second option morphine 3 mg intravenously without a ceiling dose and only limited by the appearance of secundansms if pain intensity was greater than 2 in An analog visual scale.
  • 3 gats of ketamine were administered in the postoperative period every 8 hours in the first 24 hours ( Figure 4).
  • the solution was prepared by the Hospital Pharmacy Service in simple syrup (1000 mg of ketamine hydrochloride and 500 mg Meperidine in 100 ml_), packed in topaz bottles, stored at 0-4 ° C and with an expiration date of 30 days and administered by a DUE that subsequently did not participate in the collection of study data.
  • Statistical analysis was performed with the Stata® 7 program (Stata Corporation, Computing Resource Center, College Station, Texas. USA). A descriptive study of the variables was performed and the frequency distribution of these was calculated globally. The normal distribution was tested using the Kolomogorov-Smirnov test, and the different distribution of the success and failure of the treatment in the series patients was compared between the collected variables and their possible association using the "t test for quantitative variables.
  • ASA Scale of the American Society of Anesthesiologists.
  • Pain scores by means of an analog visual scale were higher in the control group at admission to the Post-surgical Resuscitation Unit and persisted during the first 24 hours post-intervention, with statistical significance (Table 6). The evolution of pain during the first 7 days after intervention is shown in Figure 5.
  • KTM-MEP Group Ketamine and Meperidine Group. Pain intensity using a Visual Analog scale (VAS), comparison between groups. (Mean ⁇ Standard Deviation).
  • the average duration in hours of the analgesic action of ketamine engorgement was 6.93 ⁇ 1.98 hours.
  • the average need for dexketoprofen during the first 24 hours was 1 10.71 ⁇ 44.62 mg in the control group, while the ketamine group was 10.71 ⁇ 21.29 mg (p ⁇ 0.001).
  • morphine consumption statistically significant differences were also found (p ⁇ 0.01), with a lower need in the ketamine group (5.07 ⁇ 3.73 mg vs. 0.57 ⁇ 1.15 mg).
  • Example 6 Use of combined rinses (Ketamine and meperidine) in the treatment of cancer pain due to head-neck neoplasms.
  • head and neck cancer includes a group of neoplasms that are located in the paranasal sinuses, nasal cavity, nasopharynx, oropharynx or back of the throat (tonsil, soft palate and base of the tongue), hypopharynx, oral cavity , lip and salivary glands.
  • cancers of these locations are derived from squamous cells, which are thin, flat cells that cover all these anatomical structures, so these tumors are called epidermoid tumors. They represent approximately 5% of cancers in men and 2% in women. Together they are the fifth most common neoplasm in the world population. Its frequency depends on the anatomical location to which we refer.
  • squamous cell carcinoma of the head and neck are nonspecific and generally depend on the location of the tumor. Therefore, the disease often goes unnoticed to the patient and is already detected in advanced stages. Approximately 5% of patients debut with palpable cervical metastases. Approximately 60% of patients suffering from this type of cancer experience moderate or severe pain during their illness and this constitutes the main fear expressed by them and their relatives. While the total number of patients with cancer pain or related syndromes constitutes less than 5% of the population with acute or chronic pain, cancerous pain has a very special meaning for patients and their families. This underscores the importance of psychological and social aspects, which should always be taken into account in the initial evaluation and during the treatment of these patients.
  • the main symptoms are persistent sore throat, odynophagia, otalgia, persistent nasal obstruction or epistaxis, prolonged hoarseness, pains in the face or upper jaw, leukoplakia or erythroplasia, etc.
  • TCancer Type of cancer (CV: Oral cavity, Far: Faringe, Lar: Larynx).
  • RecTum Presence of tumor recurrence.
  • EVA-1 Visual Analog Scale pretreatment.
  • EVA-2 Post-treatment Analog Visual Scale.
  • Posol Number of administrations type rinse per day.
  • Example 7 Use of combined rinses (Ketamine and meperidine) in the treatment of glossopharyngeal neuralgia refractory to treatments
  • Glossopharyngeal neuralgia represents only 0.2-1, 3% of all causes of facial pain, but usually its treatment represents a difficult medical challenge.
  • the term glossopharyngeal neuralgia (NGF) was introduced by Harris in 1921. The etiology of this entity is empty, it can be idiopathic without an apparent cause, or, secondary to different processes (vascular compression, tongue-based tumors, hypopharynx and tonsils, trauma, Eagle syndrome, post-tonsillectomy, periamigdalar surgery, etc) 1 .
  • the NGF clinic manifests itself through a paroxysmal painful sensation, typically triggered by chewing, yawning, sneezing and swallowing.
  • the pain is frequently located in the posterior third of the tongue and pharynx, going to other deep structures.
  • the pain is difficult to control and the usual analgesics are not usually very effective.
  • the most effective drugs are neuromodulatory drugs (anticonvulsants and antidepressants).
  • Interventional techniques for control of the condition are neurolysis with alcohol, extracranial or intradural section of the glossopharyngeal nerve, surgical microvascular decompression and radiofrequency in conventional or pulsed mode.
  • Topical treatments have the advantage of controlling pain locally by minimizing systemic side effects.
  • agents have been tested. rinse in the oral cavity for the treatment of oropharyngeal pain such as local anesthetics, antihistamines, anti-inflammatory agents, opioids, antimicrobials or combinations thereof.
  • the results have generally been limited due, above all, to the short duration of pain relief obtained.
  • Neuralgia was considered partially resistant to conventional medical treatments and the fourth analgesic step (pulsed radiofrequency, perfusion of local anesthetics). Nuclear Magnetic Resonance showed thickening in the emergence of the glossopharyngeal that could correspond to a neurinoma. The patient refused any neurosurgical option due to the risk of sequelae.
  • Treatment with oral ketamine-Meperidine rinses was initiated at doses of 25 mg / mL-5 mg / mL (4 mL / 8 hours) after the success of the first case described above. In the last 13 months pain control has been optimal (VAS 2-3 / 10) on an outpatient basis with this treatment.
  • Example 8 Use of combined rinses (Ketamine and meperidine) in the treatment of various oropharyngeal algias compared to the use of simple rinses (Ketamine).
  • Table 8 shows a total of 9 clinical cases_with partial response to ketamine rinses and better response to ketamine-mepehdine gargles. Below we briefly describe each of these clinical cases.
  • Case 1 Male patient with a history of Alzheimer's type dementia and thromboembolic stroke. Trigeminal second branch neuralgia with poor response to oral medication with antichomatics (carbamazepine, pregabalin and topiramate) and opioids, as well as peripheral infiltrations of the trigeminal second branch of 15 months evolution. Partial pain control with ketamine rinses (VAS 4) with exacerbations of pain without a clear trigger. Better control with ketamine-mepehdine, with EVA 4 but with very minor crises. Exitus lethalis Case 2. Male patient with a diagnosis of adenocarcinoma of the pancreas.
  • Case 3 Female patient with stage lymph infiltrating ductal carcinoma with positive hormonal receptors (left modified radical mastectomy). Bone tumor recurrence in lumbar spine, dorsal and right femur. Treatment with letrozole and zoledronic acid monthly. Start of rinses of ketamine for mucositis grade 3, with better pain control with ketamine-meperidine association.
  • Case 7 Man patient diagnosed with osteosarcoma with stage IV chondroblastic differentiation with pulmonary and bone dissemination. Repeated episodes of mucositis. Fever and dysphagia clinic after chemotherapeutic treatment with pancytopenia and grade 3 mucositis. Treatment with well-oral opioids and intrathecal pump with morphine and local anesthetics. Better pain control with ketamine-meperidine association.
  • Case 8 Male patient with right hematic facial pain with poor response to various treatments with anticomcial and opioid. Very temporary response to infiltrations of peripheral trigeminal branches with complication of infection after series of infiltrations. Good response with pain control to transmucosal fentanyl withdrawn early due to excessive drowsiness. Dose tests are performed with rinses of ketamine and ketamine-meperidine and treatment should be withdrawn due to dizziness and excessive sleepiness. It is referred to the reference center for retrogasserian percutaneous rhizotomy with excellent results. Discharge from the Pain Unit.
  • Case 9 A 43-year-old male patient with a clinical history of craniocerebral trauma, generalized tonic-clonic epilepsy, smoker and drinker. Diagnosed of unresectable mouth floor (T4N3Mx) pending chemotherapy and radiotherapy. Referral by Maxillofacial Surgery Service for left submental tumor of 3 months d evolution, with ulcer of the floor of the mouth with infiltration of the ventral lingual face that causes hookworm. Very high intensity pain (VAS of 10) with paresthesia and dysesthesia in treatment with supraterapeutic doses of tramadol (900-1200 mg / 24 hours), metamizole (4000-5000 mg / 24 hours). Irruptive pain with yawning, talking and eating, currently only crushed and liquid diet.
  • VAS Very high intensity pain
  • Ketamine protocol is performed for 48 hours and subsequently with ketamine-meperidine indicating the patient better control of breakthrough pain with the latter composition and lower adverse effects type of sensation of fire and itching only with the ketamine gargles.
  • Treatment is started with simple syrup of ketamine 10 mg / ml_ and meperidine 5 mg / ml_. Tramadol is removed and therapy with transdermal fentanyl 50 mcg / 72 hours is initiated. Table 8. Comparative study
  • KETMEP Treatment with ketamine-meperidine.
  • Success KET Treatment with ketamine with a decrease in basal pain by at least 50% according to the VAS scale.
  • Success KETMEP Treatment with ketamine with a decrease in basal pain by at least 50% according to the VAS scale.
  • EVA1 Visual Analog Scale pretreatment.
  • EVA2 Post-treatment Analog Visual Scale.
  • Dose Number of administrations type rinse per day.

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Abstract

La présente invention concerne une composition et/ou un kit de préparation de celle-ci et/ou une préparation combinée comprenant une base libre ou un de ses sels pharmaceutiquement acceptables, laquelle base libre présente la formule (I) : (dans laquelle R1 est choisi dans la liste formée par hydrogène, chlore, brome, méthyl, méthoxy et hydroxy, et R représente un radical alkyle de un ou deux atomes de carbone) et un antagoniste opioïde des récepteurs mu périphériques. L'invention concerne également l'utilisation de la composition, du kit et/ou de la préparation combinée dans le traitement de la mucosite orale et de la douleur associée à la mucosite orale.
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US11692211B2 (en) 2015-04-10 2023-07-04 Comet Biorefining Inc. Methods and compositions for the treatment of cellulosic biomass and products produced thereby
US11707440B2 (en) 2017-12-22 2023-07-25 Janssen Pharmaceuticals, Inc. Esketamine for the treatment of depression
US11883526B2 (en) 2019-03-05 2024-01-30 Janssen Pharmaceutica Nv Esketamine for the treatment of depression
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US11446260B2 (en) 2013-03-15 2022-09-20 Janssen Pharmaceutica Nv Pharmaceutical composition of S-ketamine hydrochloride
US10869844B2 (en) 2014-09-15 2020-12-22 Janssen Pharmaceutica Nv Methods for the treatment of depression
US11173134B2 (en) 2014-09-15 2021-11-16 Janssen Pharmaceutica Nv Methods for the treatment of depression
US11311500B2 (en) 2014-09-15 2022-04-26 Janssen Pharmaceutica Nv Methods for the treatment of depression
US11692211B2 (en) 2015-04-10 2023-07-04 Comet Biorefining Inc. Methods and compositions for the treatment of cellulosic biomass and products produced thereby
US11980596B2 (en) 2017-09-13 2024-05-14 Janssen Pharmaceutica Nv Delivery of esketamine for the treatment of depression
US11707440B2 (en) 2017-12-22 2023-07-25 Janssen Pharmaceuticals, Inc. Esketamine for the treatment of depression
US12269903B2 (en) 2018-05-10 2025-04-08 Comet Biorefining Inc. Compositions comprising glucose and hemicellulose and their use
US11525016B2 (en) 2018-05-10 2022-12-13 Comet Biorefining Inc. Compositions comprising glucose and hemicellulose and their use
US10633461B2 (en) 2018-05-10 2020-04-28 Comet Biorefining Inc. Compositions comprising glucose and hemicellulose and their use
US11883526B2 (en) 2019-03-05 2024-01-30 Janssen Pharmaceutica Nv Esketamine for the treatment of depression
US12263184B2 (en) 2019-05-10 2025-04-01 Comet Biorefining Inc. Materials and methods for producing arabinoxylan compositions
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