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WO2013076339A1 - Compositions et préparations combinées pour le traitement de la fibromyalgie - Google Patents

Compositions et préparations combinées pour le traitement de la fibromyalgie Download PDF

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Publication number
WO2013076339A1
WO2013076339A1 PCT/ES2012/070816 ES2012070816W WO2013076339A1 WO 2013076339 A1 WO2013076339 A1 WO 2013076339A1 ES 2012070816 W ES2012070816 W ES 2012070816W WO 2013076339 A1 WO2013076339 A1 WO 2013076339A1
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WO
WIPO (PCT)
Prior art keywords
composition
preparation
combined
ketamine
pain
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/ES2012/070816
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English (en)
Spanish (es)
Inventor
Manuel CORTIÑAS SÁENZ
María Isabel CARRICONDO MARTÍNEZ
Inmaculada ALFÉREZ GARCÍA
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Servicio Andaluz de Salud
Original Assignee
Servicio Andaluz de Salud
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Filing date
Publication date
Application filed by Servicio Andaluz de Salud filed Critical Servicio Andaluz de Salud
Publication of WO2013076339A1 publication Critical patent/WO2013076339A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/13—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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid

Definitions

  • the present invention is within the field of Medicine and Pharmacy, and refers to a composition and / or a combined preparation comprising analogs of ⁇ -aminobutyric acid and arylcycloalkylamines, structurally related to cyclidines, such as ethiciclidine, phencyclidine, roliciclidine and tenociclidine, for the treatment of chronic pain. Particularly, it refers to the compositions comprising pregabalin and ketamine, and to the combined preparations of pregabalin and ketamine, for the treatment of pain, and particularly, for the treatment of fibriomyalgia.
  • the first line of treatment often includes the administration of ⁇ -opioid agonists, such as narcotics such as morphine (Anderson and Brill, 1992, Semin. Anesth. 11: 158-171).
  • narcotics such as morphine
  • SUPPL Stret-Protyl-N-phenyl-N-phenyl-N
  • narcotics opioid agonists and antagonists
  • butorphanols benzodiazepines
  • GABA stimulants GABA stimulants
  • barbiturates barbiturate analogues
  • NMDA N-methyl-D-aspartate
  • the NMDA receptor is constructed of different subunits (RN1, NR2A-D and NR3A-C), which are they can combine in different ways (NR1 in combination with 2A-D or 3A-C). Combinations of different subtypes are known to have different biophysical and pharmacological characteristics, which can influence the binding of NMDA receptor antagonists (Paoletti & Neyton, 2007. Curr Opin Pharmacol 7: 39-47). NMDA receptor antagonists were shown to reduce pain in FM (Graven-Nielsen et al., 2000. Pain 85: 483 ⁇ 191).
  • Fibromyalgia can be difficult to treat and there are usually better results if the treatment is managed by physicians from various disciplines familiar with this co nd i tion and treatment, or a multidisciplinary approach.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • analgesics can relieve some of the pain although the extent of the placebo effect in these cases has not been evaluated, probably important when dealing with patients with a long history of contacts with the health system.
  • Pregabalin (Lyrica) ® and Gabapentin (Neurotin) ® they are used successfully in the treatment of acute pain in neurological diseases such as Guillain-Barré syndrome, peripheral polyneuropathies and multiple sclerosis, as well as fibromyalgia.
  • a Cochrane review has recently been published that concludes that Gabapentin reduces pain in a third of patients with neuropathic pain.
  • These medications do not cause adverse side effects on the digestive system (stomach, intestine and liver). Its main side effect is weight gain, which in turn favors greater fatigue and pain at certain points such as knees, ankles, back, etc.
  • Ketamine or (f? S) -2- (2-chlorophenyl) -2- (methylamino) cyclohexan-1-one is a dissociative anesthetic and its main mechanism of action is considered to be through antagonism of NMDA receptors . It has analgesic properties (Domino et al., 1965, Clin. Pharmacol. Ther. 6: 279). Analgesia can be achieved by subanesthetic doses of ketamine (Bovill, 1971, Br. J. Anaesth. 43: 496; Sadove et al., 1971, Anesth. Analg. 50: 452-457).
  • ketamine in low doses is as an anti- hyperalgesia, allodynia or anti-tolerance protection agent.
  • Several groups have reported the prolonged effects of pain relievers after oral, nasal, topical or intravenous administration of ketamine and the single dose versus administration of several days or more continuous days.
  • Ketamine is known to also bind NMDA 2A subtypes to 2D and therefore can have a more favorable effect on a disease as heterogeneous as neuropathic pain, compared to NMDA receptor antagonists, with more discriminatory selectivity NMDA subtype, and his son in our study, 52.94% of the cases were classified as responders to intravenous ketamine.
  • ketamine is a great antagonistic affinity of the NMDA receptor, which in the long term blockade of the receptors and the strong inhibition of neuronal hyperexcitability that occurs in neuropathic pain.
  • a disadvantage of this indiscriminate and strong binding property is the higher proportion of side effects due to the binding of antagonists of neuronal structures that do not participate in pain.
  • the present invention provides a composition and a combination therapy of ketamine and pregabalin, which decreases the side effects associated with other cocktails of drugs used in the treatment of pain, and which is useful in the treatment of fibromyalgia.
  • a first aspect of the invention relates to a composition
  • a composition comprising, as components: a) a base or any of its pharmaceutically acceptable salts where the free base has the formula (I)
  • R1 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
  • R1 is chlorine, and R is an alkyl of a carbon atom.
  • the free base is (f? S) -2- (2-chlorophenyl) -2- (methylamino) cyclohexane-1-one, also called ketamine.
  • ketamine of the name IUPAC ⁇ RS) -2- (2-chlorophenyl) -2- (methylamino) cyclohexan-1-one, CAS number 6740-88-1, and formula (II ):
  • the ⁇ -aminobutyric acid analog is selected from the list comprising pregabalin, gabapentin, vigabatrin, or any combination thereof.
  • the ⁇ -aminobutyric acid analog is pregabalin or (S) -3- (aminomethyl) -5-methylhexanoic acid, of formula (III): formula (III) or any of its salts, prodrugs, derivatives or analogs, or any combination thereof
  • the composition is a pharmaceutical composition.
  • the composition comprises a pharmaceutically acceptable carrier.
  • the composition further comprises another active ingredient.
  • R1 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
  • R1 is chlorine, and R is an alkyl of a carbon atom.
  • the free base is (f? S) -2- (2-chlorophenyl) -2- (methylamino) cyclohexane-1-one, also called ketamine.
  • the ⁇ -aminobutyric acid analog is selected from pregabalin, gabapentin, vigabatrin, or combinations thereof.
  • the ⁇ -aminobutyric acid analog is pregabalin or (S) -3- (aminomethyl) -5-methylhexanoic acid.
  • Another aspect of the invention relates to a pharmaceutical form, hereinafter pharmaceutical form of the invention, comprising the composition of the invention, any of components a) or b) of the combined preparation of the invention, or simultaneously, the components a) and b) of the invention,
  • the pharmaceutical composition or any of components a) or b) of the combined preparation of the invention, or both is formulated as an intravenous solution or as an oral solution.
  • Another aspect of the invention relates to an intravenous solution comprising ketamine in a concentration of 0.20 to 0.40 mg / kg of the patient, and more preferably, 0.25 to 0.35 mg / kg of the patient.
  • Another aspect of the invention relates to an oral solution comprising ketamine in a concentration of 0.4 to 1.0 mg / kg of the patient, and more preferably, 0.5 to 1.0 mg / kg of the patient. More preferably, the oral solution is formulated with Ora-Sweet.
  • another aspect of the invention relates to an oral solution, comprising simple and Ora-Sweet syrup, and where the ketamine is in a concentration between 8 and 12 mg / ml, and more preferably in a concentration of 10 mg / ml.
  • ketamine 1 gr + 40 mi simple syrup with preservative + 60 mi Ora-Sweet final concentration of ketamine 10 mg / mi is used.
  • Another aspect of the invention relates to the use of the composition or the combined preparation or the pharmaceutical form of the invention, in the preparation of a medicament, or alternatively, to the composition or preparation. combined or in the pharmaceutical form of the invention, for use as a medicament.
  • Another aspect of the invention relates to the use of the composition or the combined preparation or the pharmaceutical form of the invention, in the preparation of a medicament for the treatment of pain, or alternatively, to the composition or the combined preparation or to the pharmaceutical form of the invention, for use in the treatment of pain.
  • the pain is chronic.
  • Chronic pain is pain that lasts more than six months. It can be classified as non-malignant and malignant pain.
  • Neuropathic It is usually secondary to acute injury; Its most important characteristics are the location in the territory of one or more nerves, the sensation of burning or itching and is usually accompanied by non-painful paresthesias, hyperalgesia and allodynia.
  • Vascular Related to an alteration of blood flow due to obstructive pathology or spastic vessel.
  • Pain caused by the tumor It is due to infiltration or compression on certain structures (bones, plexuses, roots, peripheral nerves, viscera).
  • Pain caused as a result of therapy (post-surgery, post-chemotherapy, post-therapy).
  • Another aspect of the invention relates to the use of the composition or the combined preparation or the pharmaceutical form of the invention, in the preparation of a medicament for the treatment of fibromyalgia, or alternatively, to the composition or to the combined preparation or the pharmaceutical form of the invention, for use in the treatment of fibromyalgia.
  • 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.
  • 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.
  • 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 the combined preparation of pregabalin and ketamine of the invention for use separately, simultaneously or sequentially as a medicine, or for the separate, simultaneous or sequential use of the combined preparation of the invention, which comprises pregabalin. and ketamine, in the preparation of a medicine.
  • Another aspect of the invention relates to the combined preparation of the invention, which comprises pregabalin and ketamine, for separate, simultaneous or sequential use in the treatment of fibromyalgia, or alternatively, for the separate, simultaneous or sequential use of the Combined preparation of the invention for the preparation of a medicament for the treatment of fibromyalgia.
  • Another aspect of the invention relates to a method of pain treatment characterized by the administration to a subject suffering from said pathology of a therapeutically effective amount of the composition or of the combined preparation or of the pharmaceutical form, as described throughout of the present invention.
  • the pain is chronic.
  • Another aspect of the present invention relates to a method of treating fibromyalgia characterized by the administration to a subject suffering from said pathology of a therapeutically effective amount, of the composition or of the combined preparation or of the pharmaceutical form, as described. in the present invention.
  • these are characterized in that the combined composition or preparation or the pharmaceutical form can be administered to the subject suffering from said pathologies, by any of the following routes: intraperitoneal, intravenous , intramuscular, subcutaneous, intracecal, intraventricular, oral, enteral, parenteral, intranasal or dermal.
  • the routes of administration are preferably the intravenous route and the oral route.
  • compositions of the present invention can be formulated for administration to an animal, and more preferably to a mammal, including the man, in a variety of ways known in the state of the art.
  • 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 may be combined with various 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.
  • 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
  • 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, in a variety of ways, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intracecal, intraventricular, oral, enteral, parenteral, intranasal or dermal.
  • 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 pregabalin and ketamine, prodrugs, derivatives or analogs of pregabalin and ketamine 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.
  • the demographic variables of age, sex, specific medication for this disorder and the associated comorbidity were collected. Pain was assessed by VAS and decreased drug use after completing the technique, and later at
  • Sleep was assessed using the MOS-Sleep scale, which includes a questionnaire with 12 items on sleep quality. In the different interviews, the quality of sleep was evaluated with a scale with 1 1 points, ranging from 0 (best possible dream) to 1 1 (worst possible dream). Mood is estimated by the Hospital Anxiety and Depression scale consisting of 14 items to assess the presence and severity of anxiety and depression. The occurrence of various adverse effects were collected. Regarding pain and sleep quality, a good response to treatment was considered a decrease in baseline values greater than 50%, a partial response to a reduction between 30-50%, and the other cases were considered as non-responders. An interview of the degree of satisfaction was carried out at the end of the treatment (Very satisfied, moderately satisfied and not satisfied).
  • the primary objective of the study was to demonstrate the effectiveness of ketamine hydrochloride in fibromyalgia cases resistant to conventional treatment.
  • the secondary objectives were to know the possible prognostic factors for the success of this treatment.
  • the indications of discretion and respect for the privacy of the patients were taken into account according to the Regulations of the Ethics Commission of the hospital.
  • Formal approval was obtained by the Ethics Commission of the hospital and the organic law for the protection of medical data was verified.
  • a descriptive and bivariate analysis was performed with the Student's t tests (quantitative variables) or ⁇ 2 (qualitative variables).
  • the ANOVA test with the Bonferroni or Scheffe correction was used if the sample sizes of the different strata were different for multiple comparisons. P values ⁇ 0.05 were considered statistically significant.
  • the data were processed using the Stata relay 7 program (Stata Corp., Collage Station, USA). Results
  • a total of 148 patients are included in the study, excluding thirteen patients for not completing the different questionnaires. In total, 768 sessions of ketamine were performed. The average age of the cohort was 57, 15 ⁇ 6.24 years, with a clear female predominance (98%). The average time from the diagnosis of FBM to the beginning of the treatment was 4.2 ⁇ 4 years, without finding statistically significant differences between the success of the treatment and the time elapsed since the diagnosis by the Rheumatology Service. (p 0.46). Due to the design of the work, the patients presented a high level of pain, with a mean baseline VAS of 7.56 ⁇ 1, 05. The baseline MOS-Sleep index was 6.31 ⁇ 1.45.
  • the mean time of onset of improvement reported by the patients was 7.87 ⁇ 2.45 days (range 1-18 days) from the first session in the unit.
  • the main adverse effect occurred were confusional states and mild dizziness in a third of the sample, in a smaller proportion they are described in a 13% increase in blood pressure, and a case of moderate deterioration of renal function.
  • the treatment for sinus tachyarrhythmia had to be discontinued, an episode that resolved after cessation of ketamine infusion.
  • the degree of satisfaction to the protocol with low doses of ketamine was 91, 45% as very satisfied.
  • Treatment with pregabalin with low doses of ketamine produces an improvement in the response to pain reduction reflected in the multiple regression analysis (ASR 6.71, 95% CI 2.92-22.98; p 0.01) , and it is dose dependent.
  • Ligand alpha 2d drugs Pregabalin treatment.
  • Tricyclic Drugs Treatment with amitriptyline, doxepin, nortriptyline, maprotiline.
  • Dual IRSN Treatment with venlafaxine, duloxetine, minalcipran.
  • Opioids Treatment with Tramadol or fentanyl.
  • Baseline VAS Basal pain measured by the analog visual scale.
  • WHO treatment Pharmacological treatment according to the analgesic ladder of the World Health Organization. Preparation of the liquid pharmaceutical form.
  • ketamine 1 gr + 40 mi simple syrup with preservative + 60 mi Ora-Sweet final concentration of ketamine 10 mg / mi 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.
  • 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.
  • -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%)).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique, une préparation combinée ou une forme pharmaceutique qui comprend un analogue de l'acide γ-aminobutyrique et de la kétamine, et qui est destinée à être utilisée dans l'élaboration d'un médicament utile dans le traitement de la douleur chronique et de la fibromyalgie.
PCT/ES2012/070816 2011-11-22 2012-11-22 Compositions et préparations combinées pour le traitement de la fibromyalgie Ceased WO2013076339A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES201131879 2011-11-22
ESP201131879 2011-11-22

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WO2013076339A1 true WO2013076339A1 (fr) 2013-05-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2596592A (en) * 2020-07-03 2022-01-05 Alkaloid Ad Skopje Pharmaceutical formulation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020115705A1 (en) * 1997-09-08 2002-08-22 Leslie Magnus-Miller Analgesic compositions comprising anti-epileptic compounds and methods of using same
US20050095277A1 (en) * 2003-06-25 2005-05-05 Binnur Ozturk Neuropathy cream
WO2005102390A2 (fr) * 2004-04-22 2005-11-03 Pfizer Japan, Inc. Combinaisons comprenant des ligands alpha-2-delta et des antagonistes des recepteurs de nmda
US20110039875A1 (en) * 2007-08-06 2011-02-17 Trinity Laboratories, Inc. Pharamaceutical compositions for treating chronic pain and pain associated with neuropathy
US20110178177A1 (en) * 2008-09-27 2011-07-21 Taraxos Inc. Topical formulations for treatment of neuropathy

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020115705A1 (en) * 1997-09-08 2002-08-22 Leslie Magnus-Miller Analgesic compositions comprising anti-epileptic compounds and methods of using same
US20050095277A1 (en) * 2003-06-25 2005-05-05 Binnur Ozturk Neuropathy cream
WO2005102390A2 (fr) * 2004-04-22 2005-11-03 Pfizer Japan, Inc. Combinaisons comprenant des ligands alpha-2-delta et des antagonistes des recepteurs de nmda
US20110039875A1 (en) * 2007-08-06 2011-02-17 Trinity Laboratories, Inc. Pharamaceutical compositions for treating chronic pain and pain associated with neuropathy
US20110178177A1 (en) * 2008-09-27 2011-07-21 Taraxos Inc. Topical formulations for treatment of neuropathy

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2596592A (en) * 2020-07-03 2022-01-05 Alkaloid Ad Skopje Pharmaceutical formulation

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