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WO2008138968A2 - Forme posologique comprenant de la 10-[(3s)-1-azabicyclo [2.2.2] oct-3-ylméthyl] - 10h-phénothiazine pour administration orale d'une dose quotidienne de 1mg à 3 mg - Google Patents

Forme posologique comprenant de la 10-[(3s)-1-azabicyclo [2.2.2] oct-3-ylméthyl] - 10h-phénothiazine pour administration orale d'une dose quotidienne de 1mg à 3 mg Download PDF

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Publication number
WO2008138968A2
WO2008138968A2 PCT/EP2008/055971 EP2008055971W WO2008138968A2 WO 2008138968 A2 WO2008138968 A2 WO 2008138968A2 EP 2008055971 W EP2008055971 W EP 2008055971W WO 2008138968 A2 WO2008138968 A2 WO 2008138968A2
Authority
WO
WIPO (PCT)
Prior art keywords
azabicyclo
ylmethyl
oct
dosage form
drug
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/EP2008/055971
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English (en)
Other versions
WO2008138968A4 (fr
WO2008138968A3 (fr
Inventor
Thierry Clerc
Alain Delarue
Christophe Przybylski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of WO2008138968A2 publication Critical patent/WO2008138968A2/fr
Publication of WO2008138968A3 publication Critical patent/WO2008138968A3/fr
Publication of WO2008138968A4 publication Critical patent/WO2008138968A4/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • Dosage form comprising 10- [ (3S) -1-azabicyclo [2.2.2 ] oct-3- ylmethyl] -lOfl-phenothiazine, provided in a form suitable for oral administration of a daily dose of 1 mg to 3 mg
  • the present invention relates to the (S) -enantiomer of mequitazine (10- [ (3S) -1-azabicyclo [2.2.2] oct-3-ylmethyl] - lOH-phenothiazine) and to the use of same in a daily dose of 1 mg to 3 mg to prevent and/or treat allergic disorders.
  • Mequitazine is a substituted phenothiazine derivative of the following formula:
  • the mequitazine molecule has an asymmetrical carbon resulting in two different spatial configurations:
  • levorotatory (S) -enantiomer levorotatory (S) -enantiomer
  • mequitazine exists in the form of two optically active enantiomers : the levorotatory enantiomer of configuration (S) (10- [ (3S) -1-azabicyclo [2.2.2 ] oct-3- ylmethyl] -lOH-phenothiazme) and the dextrorotatory enantiomer of configuration (R) (10- [(3R)-I- azabicyclo [2.2.2 ] oct-3-ylmethyl] -lOi ⁇ - phenothiazme) .
  • Mequitazine is a phenothiazme-class Hi antihistamine used to prevent or treat various symptoms of allergic origin such as: allergic reactions, namely the symptomatic treatment of cutaneous, ocular or ENT immediate-type hypersensitivity reactions and of allergic reactions during desensitization treatments, allergic, seasonal or perennial rhinitis, in particular hay fever, vasomotor rhinitis, • allergic conjunctivitis, pruritus or dermatological symptoms of allergic or viral origin, urticaria, in particular acute urticaria, drug allergy.
  • allergic reactions namely the symptomatic treatment of cutaneous, ocular or ENT immediate-type hypersensitivity reactions and of allergic reactions during desensitization treatments
  • allergic, seasonal or perennial rhinitis in particular hay fever, vasomotor rhinitis
  • allergic conjunctivitis pruritus or dermatological symptoms of allergic or viral origin
  • urticaria in particular acute urticaria, drug allergy.
  • Mequitazine is characterized by:
  • a sedative effect of centrally histaminic and adrenolytic origin an effect less than that of other first-generation Hi antihistamines.
  • the absence of sedation has been demonstrated at a dose of 5 mg in a limited group of healthy volunteers. It could not be verified in certain more sensitive subjects (children, the elderly) .
  • Mequitazine is typically non-sedative at a dose of 5 mg, but the therapeutic range is narrow because it is sedative at 10 mg.
  • Antihistamines are widely used as a first course in the treatment of allergic rhinitis.
  • the principal criticism of this product class is that most treatments cause drowsiness or other sedative phenomena. Patients and practitioners are eagerly awaiting an effective compound that lacks a sedative effect.
  • mequitazine is prescribed at a dose of 10 mg/day for the symptomatic treatment of pollmosis, perennial allergic rhinitis and urticaria.
  • the inventors have discovered that the (S) -configuration levorotatory enantiomer of mequitazine is effective in the treatment of allergic rhinitis at a dose as low as 2.5 mg/day/patient, i.e., at a dose that is only one-quarter that of the dose typically prescribed.
  • This very low-dose activity makes possible, treatments that are safer in use than other compounds of the same class.
  • no adverse effects such as sedation, cholinergic effects or interference with satiety, have been reported.
  • the first object of the present invention is a dosage form comprising 10- [ (3S) -1-azabicyclo [2.2.2 ] oct-3- ylmethyl] -lOH-phenothiazine, or at least one pharmaceutically acceptable salt of same, characterized in that it provides in a suitable form for oral administration a daily dose of 1 mg to 3 mg, preferably 1.5 mg to 2.5 mg .
  • Dosage form means the individual form in which the active ingredient and the excipients are formulated to constitute a drug. It refers to the final physical appearance of the drug as used by a patient.
  • “Pharmaceutically acceptable salt” means any salt that preserves the effectiveness and the properties of an active ingredient and that does not cause side effects.
  • the salt is a pharmaceutically acceptable mineral or organic acid.
  • Preferred but non-limiting examples include halogen hydrates such as hydrochloride and hydrobromide; fumarate; maleate; oxalate; citrate; methanesulfonate; glutamate; tartrate; mesylate; and hydrates of same.
  • the preferred mequitazme (S) -enantiomer salt is mequitazme hydrochloride .
  • the dosage form of the invention is provided as a daily dosage unit comprising 1 mg to 3 mg, preferably 1.5 mg to 2.5 mg, of 10- [(3S)-I- azabicyclo [2.2.2 ] oct-3-ylmethyl] -lOff-phenothiazine, or at least one pharmaceutically acceptable salt of same.
  • the dosage form of the invention can be provided in any form suitable for administration of the active ingredient by oral route, most notably in solid or liquid form.
  • the preferred forms are tablets, gelatin capsules, syrups, suspensions or solutions.
  • a liquid form such as a syrup or a suspension
  • said dosage form preferably contains between 0.1 mg/ml and 10 mg/ml, more preferably roughly 1 mg/ml, of 10- [(3S)-I- azabicyclo [2.2.2 ] oct-3-ylmethyl] -lOH-phenothiazme, or at least one pharmaceutically acceptable salt of same.
  • the dosage form of the invention can comprise a mixture of (R)- and (S) -enantiomers of 10- [1- azabicyclo [2.2.2 ] oct-3-ylmethyl] -lOH-phenothiazme .
  • said mixture of enantiomers contains between 95% and 100% by weight of the (S) -enantiomer, preferably between 96% and 100% by weight of the (S) -enantiomer, more preferably between 97% and 100% by weight of the (S)- enantiomer, even more preferably between 98% and 100% by weight of the (S) -enantiomer, and more preferably yet between 99% and 100% by weight of the (S) -enantiomer .
  • the dosage form of the invention is essentially free of the (R) - enantiomer, i.e., preferably said enantiomer mixture is essentially pure (S) -enantiomer .
  • the dosage form of the invention minimizes the appearance of adverse effects, most notably sedative effects .
  • the second object of the present invention is the use of 10- [ (3S) -1-azabicyclo [2.2.2] oct-3-ylmethyl] -10H- phenothiazme, or at least one pharmaceutically acceptable salt of same, to prepare a drug provided in a dosage form suitable for oral administration of a daily dose of 1 mg to 3 mg, preferably 1.5 mg to 2.5 mg, to prevent and/or treat allergic disorders such as: allergic reactions, namely the symptomatic treatment of cutaneous, ocular or ENT immediate-type hypersensitivity reactions and of allergic reactions during desensitization treatments, allergic, seasonal or perennial rhinitis, in particular hay fever, • vasomotor rhinitis, allergic conjunctivitis, pruritus or dermatological symptoms of allergic or viral origin, urticaria, in particular acute urticaria, • drug allergy.
  • allergic reactions namely the symptomatic treatment of cutaneous, ocular or ENT immediate-type hypersensitivity reactions and of allergic reactions during desensitization treatments
  • the present invention also has as an object the use of 10- [ (3S) -1-azabicyclo [2.2.2] oct-3-ylmethyl] -10H- phenothiazme, or at least one pharmaceutically acceptable salt of same, to prepare a drug provided in a dosage form suitable for oral administration of a daily dose of 1 mg to 3 mg, preferably 1.5 mg to 2.5 mg, to prevent and/or treat dermatological symptoms caused by a release of histamine or by an abnormally high level of IgE, such as chronic idiopathic urticaria.
  • said drug is provided as a daily dosage unit comprising 1 mg to 3 mg, preferably 1.5 mg to 2.5 mg, of 10-[(3S)-I- azabicyclo [2.2.2] oct-3-ylmethyl] -lOH-phenothiazine, or at least one pharmaceutically acceptable salt of same. Because of the low dose of mequitazine contained therein, said drug minimizes the appearance of adverse effects, most notably sedative effects.
  • Said drug can be used in combination with another active ingredient selected among antihistamines, lipoxygenase inhibitors, anti-mflammato ⁇ es, inhibitors of pro-inflammatory cytokine release, leukotriene receptor antagonists, or compounds that control the release of mediators from mast cells, such as leukot ⁇ enes, prostaglandins, thromboxane A2 or platelet-activating factor (PAF) .
  • another active ingredient selected among antihistamines, lipoxygenase inhibitors, anti-mflammato ⁇ es, inhibitors of pro-inflammatory cytokine release, leukotriene receptor antagonists, or compounds that control the release of mediators from mast cells, such as leukot ⁇ enes, prostaglandins, thromboxane A2 or platelet-activating factor (PAF) .
  • PAF platelet-activating factor
  • EXAMPLE 1 Activity of 10- [ (3S) -1-azabicyclo [2.2.2 ] oct-3- ylmethyl] -lOE-phenothiazine ("L-mequitazme”) on seasonal allergic rhinitis in man.
  • Mequitazine is a racemic mixture comprised of two enantiomers m equal amounts (50/50) : (S) form (levorotatory) and (R) form (dextrorotatory) .
  • the purpose of this study is to evaluate the effectiveness and the dose-response relationship of L-mequitazine ((S)- enantiomer) in a clinical setting among patients with hay fever .
  • the products administered daily by oral route were as follows: placebo, 2.5 mg L-mequitazme tablet, 5 mg L- mequitazme tablet, 7.5 mg L-mequitazme tablet and 10 mg L-mequitazme tablet.
  • the reference product (racemic mixture of the (S)- and (R) -enantiomers of mequitazme) was also administered by oral route at a dose of 10 mg per patient per day.
  • the tablets were masked in capsules of similar appearance.
  • the duration of the treatment was 14 consecutive days.
  • Treatment effectiveness was analyzed by measuring changes in nasal symptom score (NSS) (sternutation, rhmorrhea, nasal pruritus, nasal obstruction) at D7.
  • NSS nasal symptom score
  • Table 1 Subjects by treatment type at time of evaluation.
  • Table 2 Demographic characteristics of the population studied.
  • the principal criterion of the study is to evaluate the influence of various doses of L-mequitazme on changes in the so-called nasal symptom score (NSS) at D7.
  • the score is based on the investigator's rating, on a scale from 0 to 3, of the following: pruritus, sternutation, discharge, nasal obstruction.
  • the study is regarded as highly satisfactory since, without major deviation, it strengthens the quality of subsequent interpretations.
  • Table 3 The results are presented in table 3 below.
  • the level of activity obtained in the placebo group is widely known and documented for this type of symptomatology. This effect is partly due to the natural regression of the pathology.
  • EXAMPLE 2 Absence of induction of sedation after effective treatment for 14 days at a 2.5 mg dose of 10-[(3S)-I- azabicyclo[2.2.2] oct-3-ylmethyl] -lOff-phenothiazine ("L- mequitazine”) .
  • Table 4 presents the sedative-related events that appeared during treatment as a function of the dose of the compound administered.
  • This phase III study was carried-out in order to evaluate the effectiveness of V0114 CP 2.5mg tablet in the treatment of seasonal allergic rhinitis. It was a randomized prospective, multi-centric, international, in two parallel groups, double-blind, placebo-controlled study including 474 randomised patients.
  • the primary objective was to demonstrate the efficacy of a 2-weeks treatment by the antihistamine V0114CP 2.5 mg daily in reducing symptoms during seasonal allergic rhinitis.
  • the secondary objectives were to evaluate the percentage of success to treatment, the onset of action, the clinical global improvement, and finally, to analyse the systemic tolerance of V0114CP 2.5 mg .
  • the primary criterion was defined by the evolution over the 14 days treatment period of the reflective (12 hours) patient-rated nasal symptom score NSS
  • EXAMPLE 4 Activity of V0114 (10- [(3S)-I- azabicyclo [2.2.2 ] oct-3-ylmethyl] -lOS-phenothiazme) , is devoid of any sedative effect; this assessment has been proven in vitro in a specific model of blood-brain barrier. V0114 was less able to cross the blood-brain barrier than the dextrogyral enantiomers.
  • the aim of the study was to underline the transport ability of V0114 across the blood-brain barrier using a relevant and predictive blood-brain barrier in vitro model (Cecchelli et al . , 1999).
  • the model consisted in brain capillary endothelial cells co-cultured with glial cells, thereby closely mimicking the in vivo conditions (Lundquist et al . , 2002) . Endothelial cells have been cultured in the upper compartment on a filter and glial cells in the lower compartment of the plastic of a six-well plate.
  • endothelial cells retained all the endothelial markers (factor VIII - related antigen, non-thrombogenic surface, production of prostacyclin, angiotensin converting enzyme activity) and the characteristics of the blood-brain barrier (presence of tight junctions, paucity of pmocytotic vesicles, monoamine oxidase activity, '- glutamyltranspeptidase activity and P-glycoprotem (Meresse et al.,1989; Dehouck et al . , 1992; Fenart et al., 1998).
  • V0114 and V0162 were not toxic for the blood-brain barrier integrity at the tested concentrations.
  • the results showed that the permeability coefficient obtained for the compound V0114 indicated a low brain penetration at the concentration of 2 ⁇ M (1.49 +_ 0.21 x 10 " 3 cm/mm) .
  • the permeability coefficient obtained for the compound V0162 indicated a good brain penetration at the concentrations of 2 ⁇ M (3.61 4; 0.87 x 10 "3 cm/mm).
  • EXAMPLE 5 Activity of V0114 (10- [(3S)-I- azabicyclo [2.2.2 ] oct-3-ylmethyl] -lOi ⁇ -phenothiazine) , is devoid of any sedative effect; this assessment has been proven in a specifically-designed clinical study in "real- life" conditions.
  • the primary objective was to evaluate the dose effect relationship of 3 different doses of V0114 on actual driving performance (road tracking test) .
  • the main criterion was the standard deviation of lateral position (SDLP).
  • SDLP standard deviation of lateral position
  • the secondary objectives were respectively to compare the effects of 3 different doses of V0114 to placebo on actual driving performance, and to compare the effects of 3 different doses of V0114 to mequitazine (as racemic mixture) 10 mg on actual driving performance
  • This signal has been digitised at a rate of 4 Hz and stored on an onboard computer disk file for later editing analysis.
  • the off line editing routine involved removal of all data segments that reveal signal loss, disturbance or occurrence of passing manoeuvres. The remaining data have been used to calculate means and variances for lateral position and speed (SP) .
  • Standard deviation of lateral position (SDLP) has been taken as the primary outcome variable. SDLP is a measure of road tracking error, m practical terms, a composite index of allowed weaving, swerving and overcorrecting .
  • the test duration was approximately 1 hour. A training test of at least 15 minutes has been done during the screening period.
  • Results are expressed as means; differences vs. placebo , p ⁇ 0.05; **: p ⁇ 0.01; ***: p ⁇ 0.001; ns : non significant.
  • the results show that at 2.5mg and 5mg there is no significant effect onto the standard deviation of the lateral position. In addition, no effect on immediate recall during driving is observed. Finally, no interaction with alcohol can be seen at the aforesaid doses. When considering the lOmg dose, significant impairing effects on driving appears. At the recommended therapeutic dosage of 2.5mg, V0114 is completely devoid of any deleterious effect onto vigilance. Moreover, there is no interaction or additive effect with alcohol.
  • L-mequitazine is active in the treatment of symptoms associated with allergies such as rhinitis at one-quarter the dose of the racemic mixture. At this dose and with this activity, the compound has no sedative effect.

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Abstract

L'invention porte sur une forme posologique comprenant de la 10-[(3S)-1-azabicyclo [2.2.2] oct-3-ylméthyl] - 10H-phénothiazine, ou au moins l'un de ses sels pharmacocompatibles, et caractérisée en ce qu'elle se présente sous une forme appropriée à l'administration orale d'une dose quotidienne de 1mg à 3 mg, et à son incorporation à un médicament prévenant ou traitant des troubles allergiques, et plus particulièrement la rhinite
PCT/EP2008/055971 2007-05-15 2008-05-15 Forme posologique comprenant de la 10-[(3s)-1-azabicyclo [2.2.2] oct-3-ylméthyl] - 10h-phénothiazine pour administration orale d'une dose quotidienne de 1mg à 3 mg Ceased WO2008138968A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0755075 2007-05-15
FR0755075A FR2916142A1 (fr) 2007-05-15 2007-05-15 Forme pharmaceutique comprenant du (10-[(3s)-1-azabicyclo [2.2.2]oct-3-ylmethyl]-10h-phenothiazine se presentant sous une forme appropriee pour l'administration d'unde dose journaliere comprise entre 1 et 3 mg

Publications (3)

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WO2008138968A2 true WO2008138968A2 (fr) 2008-11-20
WO2008138968A3 WO2008138968A3 (fr) 2009-05-22
WO2008138968A4 WO2008138968A4 (fr) 2009-07-02

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AR (1) AR066587A1 (fr)
FR (1) FR2916142A1 (fr)
TW (1) TW200906417A (fr)
WO (1) WO2008138968A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019099995A1 (fr) * 2017-11-17 2019-05-23 Neurana Pharmaceuticals, Inc. Méthodes d'administration de tolpérisone

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2522660A1 (fr) * 1982-03-05 1983-09-09 Pharmuka Lab Isomere levogyre de la mequitazine, son procede de preparation et medicaments le contenant
JPH07188040A (ja) * 1993-12-27 1995-07-25 Taisho Pharmaceut Co Ltd 鼻炎治療用組成物
FR2772029B1 (fr) * 1997-12-08 2000-02-25 Pf Medicament Procede de preparation de la mequitazine et nouvel intermediaire de synthese
JP2000191536A (ja) * 1998-10-20 2000-07-11 Taisho Pharmaceut Co Ltd メキタジン配合内服固形製剤
WO2005037245A2 (fr) * 2003-10-21 2005-04-28 Direct-Haler A/S Medication a administration par voies multiples, servant a traiter une rhinite et un asthme
JP2006096749A (ja) * 2004-08-31 2006-04-13 Takeda Chem Ind Ltd 感冒用医薬組成物
FR2896690B1 (fr) * 2006-01-30 2008-05-02 Pierre Fabre Medicament Sa Utilisation de l'enantiomere(s) de la mequitazine pour la preparation d'un medicament, tout en limitant la toxicite genomique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019099995A1 (fr) * 2017-11-17 2019-05-23 Neurana Pharmaceuticals, Inc. Méthodes d'administration de tolpérisone
CN111886007A (zh) * 2017-11-17 2020-11-03 纽兰娜制药股份有限公司 托哌酮的施用方法

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AR066587A1 (es) 2009-09-02
WO2008138968A4 (fr) 2009-07-02
TW200906417A (en) 2009-02-16
WO2008138968A3 (fr) 2009-05-22
FR2916142A1 (fr) 2008-11-21

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