WO2008138968A2

WO2008138968A2 - Dosage form comprising 10-[(3s)-1-azabicyclo[2.2.2]oct-3-ylmethyl]-10h-phenothiazine, provided in a form suitable for oral administration of a daily dose of 1 mg to 3 mg

Info

Publication number: WO2008138968A2
Application number: PCT/EP2008/055971
Authority: WO
Inventors: Thierry Clerc; Alain Delarue; Christophe Przybylski
Original assignee: Pierre Fabre Medicament SA
Current assignee: Pierre Fabre Medicament SA
Priority date: 2007-05-15
Filing date: 2008-05-15
Publication date: 2008-11-20
Anticipated expiration: 2009-11-15
Also published as: AR066587A1; WO2008138968A4; TW200906417A; WO2008138968A3; FR2916142A1

Abstract

The invention relates to a dosage form comprising 10-[(3S)-1-azabicyclo[2.2.2]oct-3-ylmethyl]-10H-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 1mg to 3 mg, and to the use of same to prepare a drug to prevent and/or treat allergic disorders, most notably allergic rhinitis.

Description

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 | dextrorotatory (R) -enantiomer Thus, 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] -lOiϊ- phenothiazme) .

The two enantiomers of mequitazine can be separated and isolated according to processes described in patent applications EP 0089860 or EP 0093643, for example. 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. In France, the racemic mixture of mequitazine is marketed m the form of 5 mg or 10 mg tablets (Pπmalan® or Quitadπll®) or in syrup form (Pπmalan®) . 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.

An anticholinergic effect, which is the source of peripheral adverse effects.

Analysis of the properties of the two enantiomers has shown that the levorotatory enantiomer of configuration (S) exhibits a very high affinity for histaminergic Hi receptors, whereas the other enantiomer exhibits higher affinity and selectivity for cholinergic receptors.

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. In adults, mequitazine is prescribed at a dose of 10 mg/day for the symptomatic treatment of pollmosis, perennial allergic rhinitis and urticaria.

Unexpectedly, 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. At this level of effectiveness against the pathology, no adverse effects, such as sedation, cholinergic effects or interference with satiety, have been reported.

Thus, 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. Preferably, 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.

According to the present invention, the preferred mequitazme (S) -enantiomer salt is mequitazme hydrochloride . According to one embodiment, 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.

When the dosage form of the invention is provided m 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 . In such a case, 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 . In one particularly preferred embodiment, the dosage form of the invention is essentially free of the (R) - enantiomer, i.e., preferably said enantiomer mixture is essentially pure (S) -enantiomer .

Because of the low dose of mequitazme contained therein, 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.

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. According to one particular embodiment, 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-mflammatoπes, inhibitors of pro-inflammatory cytokine release, leukotriene receptor antagonists, or compounds that control the release of mediators from mast cells, such as leukotπenes, prostaglandins, thromboxane A2 or platelet-activating factor (PAF) .

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 .

1.1) Study description The results presented below were obtained during a controlled, randomized, double-blind study of mequitazine versus placebo, evaluating the dose-response relationship of L-mequitazme at doses of 2.5 mg, 5 mg, 7.5 mg and 10 mg in the treatment of seasonal allergic rhinitis. The principal objective of this study is to evaluate the clinical effectiveness of L-mequitazine in the treatment of seasonal allergic rhinitis by analyzing the effects of L-mequitazme at various doses versus placebo. In parallel, the activity of a racemic mixture of mequitazme was compared to that of placebo to determine the relative effectiveness of L-mequitazme .

In this study, 431 patients were selected according to the following criteria: female or male patients between 18 and 65 years of age suffering from seasonal allergic rhinitis. Symptomatology was defined by a medical history of seasonal rhinitis accompanied by symptoms for at least two years. Allergic sensitivity was confirmed by a positive prick test for allergy to Gramineae pollen and/or to specific IgE class 3. Each patient included in the study had a nasal symptom score greater than or equal to 6 at inclusion (maximum score: 12) .

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. The following secondary criteria were also analyzed: changes m nasal symptom score at D14, changes in non-nasal symptom score (NNSS) (lacrimation, ocular itching, eye redness, palate pruritus) at D7 and D14; - changes in total symptom score (TSS=NSS+NNSS) at D7 and D14, changes m "reduced" NSS (without symptom of nasal obstruction) at D7 and D14, NSS values consistent with the patient's individual medical history (action onset), success rate (reduction of NSS by half without early discontinuation due to adverse effects or ineffectiveness) ; individual rhinitis symptoms evaluated at D7 and Dl 4; overall assessment by the patient and the investigator at D14.

1.2) Results

Four-hundred thirty-one patients were treated according to the protocol described above. The treatment conditions are presented in table 1.

Table 1: Subjects by treatment type at time of evaluation.

The demographic characteristics of the patients included m this study are presented m table 2 below.

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. Qualitatively, the study is regarded as highly satisfactory since, without major deviation, it strengthens the quality of subsequent interpretations. The results are presented in table 3 below.

Table 3: Activity of low-dose L-mequitazine on seasonal allergic rhinitis in man

Summary of effectiveness by protocol, differences analyzed vs. placebo; #: 0.05<p<0.1; *: p<0.05.

Racemic mequitazine, at a dose of 10 mg, was effective vs. placebo on allergic rhinitis in man. This result validates the clinical study since it is obtained with a positive reference. 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.

Regarding analysis of the study' s principal criterion, effectiveness is achieved in a statistically significant manner at a dose as low as 2.5 mg. This study shows that at a dose one-quarter that of a dose of racemic mequitazine, L-mequitazine is effective on rhinitis and its associated symptoms. Doses higher than 2.5 mg per patient per day are roughly equally effectrve, even rf the results are not statistically significant for doses of 5 mg and 7.5 mg . Finally, the maximum dose tested in this study (10 mg) is again noted to be effective vs. placebo.

In conclusion, the antihistamine activity of 2.5 mg and 10 mg doses of L-mequitazine, repeated over a period of 14 days, was established on seasonal allergic rhinitis in man. The effectiveness of the compound is such that its maximum activity is achieved at the lowest dose tested. The soundness of this clinical study is established and the study is validated by the activity observed in the racemic group, m which activity was expected.

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") .

During the study described in example 1, particular attention was given to monitoring any sedative phenomena which might appear during treatment. Table 4 below presents the sedative-related events that appeared during treatment as a function of the dose of the compound administered.

Table 4: Incidence of sedation after treatment with L- mequitazme in man

Significant differences: #: 0.05<p<0.1; *:p<0.05,

EXAMPLE 3: Activity of V0114 (10- [ (3S) -1- azabicyclo[2.2.2] oct-3-ylmethyl] -lOiϊ-phenothiazine) on seasonal allergic rhinitis m man ; study of chosen dose in phase III

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 . Patients included in the study suffered from a seasonal allergic rhinitis to grass pollen grain defined by the following criteria. 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

(sneezing, rhinorrhea, nose itching, nasal blockade) evaluated daily in the evening. Analysis of daily NSS over

2 weeks was done using Mixed Model for Repeated Measures

(MMRM) approach, with baseline NSS as a covaπate (main analysis) in the full set analysis population.

The results of the main analysis of the Patient-Rated Reflective NSS over 2-weeks are represented in appended Figure 1.

As shown in Figure 1, a significant treatment effect (p=0.029) was noted with a significant effect of the baseline level, of the day and of centres (p <0.001, p <0.001 and p=0.009) .

No serious adverse event have been reported during the study. The efficacy of 2.5 mg repeated oral doses of V0114 have been confirmed in patient exhibiting symptoms of seasonal or intermittent rhinitis. In addition, few adverse events were reported at this dosage. The number of patients with at least one treatment emergent adverse event was inferior in the V0114 arm than m the placebo group. Finally there was no difference between placebo and active arm when considering the somnolence or anticholinergic adverse effect, confirming the good tolerance of the treatment . 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. Under these conditions, 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).

By growing primary endothelial cells on one side of a porous filter and glial cells on the other, the environment that exists in vivo and so induce most of the blood-brain barrier characteristics can be obtained. Of these characteristics, one is of major importance for studying drug transport to the brain; in vivo, brain capillary endothelial cells connected by tight junctions form a continuous lining in the capillary wall that prevents paracellular flux of solutes. The immunofluorescent results clearly demonstrated that brarn capillary express actin,

ZO-I (zonula occludens) , ZO-2, ppl20, catenin, F.actin and occluding continuously at cell-to-cell contacts. This continuous staining of occludm at the cell border indicated that these cells were highly differentiated endothelial cells of cerebral origin. These and previously published results demonstrating high electrical resistance

(500-800. ohm. cm^"2) and low permeability, indicated a highly differentiated model that is suited to the study of drug transport. Furthermore, there is a very close correlation between the drug permeability obtained in vivo and in vitro .

In this experiments the permeability of V0114 (levogyral enantiomers) and V0162 (dextrogyral enantiomers) have been compared.

The effect of V0114 and V0162 for the integrity of the blood-brain barrier was studied. Each compound was applied on the endothelial cells of the in vitro blood-brain barrier model at the concentrations of 0.1 μM, 1 μM and 10 μM. Both compounds 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 μM (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 μM (3.61 4; 0.87 x 10^"3 cm/mm).

Taken together these in vitro results showed that V0114 was less able to cross the blood-brain barrier than the dextrogyral enantiomer. According to this it is likely that V0114 should be more devoid of central side-effect than V0162. This non-clinical evidence is confirmed in the clinical study hereafter (example 5) .

EXAMPLE 5 : Activity of V0114 (10- [(3S)-I- azabicyclo [2.2.2 ] oct-3-ylmethyl] -lOiϊ-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). 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

(Vermeeren A.et al., 1998; Vuurman E. F. P. M. et al . , 2004). Finally, it was of interest to evaluate the interaction of

V0114 with alcohol on actual driving performance. The evaluation of the putative effect of the compound on cognitive test was performed using the Word Learning Task

(WLT) . At last, the systemic tolerance has been analysed. It was a controlled, randomised, double blind, 5 way latin square design: 3 doses of V0114 (2.5, 5 and 10 mg) , mequitazine (racemate, L0013) 10 mg as a reference product and placebo as negative control. The different products have been tested without alcohol, then with alcohol. Effects of the different products have been evaluated after a single dose (around the Tmax of the products, i.e. 6 hours) . In the Road Tracking Test, the subjects operated a specially instrumented vehicle over a 100 km primary highway circuit while maintaining a constant speed (95 km.h ^l) and a steady lateral position between the delineated boundaries of the right (slower) traffic lane. A video camera mounted at the rear back of the car continuously recorded the lateral position of the vehicle relative to the left lane-line. 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. At each period of treatment, subjects performed two driving tests. The first one, without alcohol, started 5 hours after drug intake; the second one, with alcohol, started 7 hours and 15mm after drug intake and 45 minutes after alcohol drinking (ethyl alcohol 96% in orange juice) adjusted for each subject. Effects of V0114 on driving and cognitive performance, per protocol analysis onto 25 healthy volunteers

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. In the present test, no alteration of the cognitive functions appears after treatment with V0114 at the dose that will be used in clinical practice for treatment of allergic relieving symptoms. First/second-generation antihistamines have been shown to produce significant performance impairment in psychomotor and driving tests. Taken together the aforesaid results show that V0114 overcomes the sedative side-effects of the first/second-generation antihistamines. These results show that at a dose at which activity is optimal, L-mequitazme does not induce sedative phenomena in the treated population. Indeed, at this dose there is no significant difference compared to placebo.

Conclusion: unexpectedly, 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.

Claims

1. A dosage form comprising 10-[(3S)-I- azabicyclo[2.2.2] oct-3-ylmethyl] -lOff-phenothiazine, or at least one pharmaceutically acceptable salt of same, characterized in that it provides m a suitable form for oral administration a daily dose of 1 mg to 3 mg.

2. The dosage form according to claim 1, characterized in that it provides in a suitable form for oral administration a daily dose of 1.5 mg to 2.5 mg .

3. The dosage form according to claim 1, characterized in that it is provided as a daily dosage unit comprising 1 mg to 3 mg of 10-[(3S)-I- azabicyclo[2.2.2] oct-3-ylmethyl] -lOff-phenothiazme, or at least one pharmaceutically acceptable salt of same.

4. The dosage form according to claim 3, characterized m that said daily dosage unit comprises 1.5 mg to 2.5 mg of 10- [ (3S) -1-azabicyclo [2.2.2 ] oct-3- ylmethyl] -lOH-phenothiazme, or at least one pharmaceutically acceptable salt of same.

5. The dosage form according to any of the preceding claims, characterized in that it is provided in the form of a tablet, gelatin capsule, syrup, suspension or solution.

6. The dosage form according to any of the preceding claims, characterized in that it comprises a mixture of (R)- and (S) -enantiomers of 10- [1- azabicyclo[2.2.2] oct-3-ylmethyl] -10-ff-phenothiazine containing between 95% and 100% by weight of the (S)- enantiomer, preferably between 99% and 100% by weight of the (S) -enantiomer .

7. The dosage form according to claim 6, characterized in that said mixture of enantiomers of

10- [1-azabicyclo [2.2.2] oct-3-ylmethyl] -10H- phenothiazine is essentially pure (S) -enantiomer .

8. Use of 10- [ (3S) -1-azabicyclo [2.2.2] oct-3- ylmethyl] -lOH-phenothiazine, 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 to prevent and/or treat allergic disorders, most notably allergic rhinitis.

9. Use according to claim 8, characterized in that said drug is provided in a dosage form suitable for oral administration of a daily dose of 1.5 mg to 2.5 mg.

10. Use according to claim 8 or claim 9, characterized in that said drug is provided as a daily dosage unit comprising 1 mg to 3 mg of 10- [ (3S)-I- azabicyclo [2.2.2] oct-3-ylmethyl] -lOϋ-phenothiazme, or at least one pharmaceutically acceptable salt of same.

11. Use according to claim 10, characterized m that said drug is provided as a daily dosage unit comprising 1.5 mg to 2.5 mg of 10-[(3S)-I- azabicyclo[2.2.2] oct-3-ylmethyl] -10-ff-phenothiazine, or at least one pharmaceutically acceptable salt of same.

12. Use according to any of claims 8 to 11, characterized in that said drug is 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.

13. Use according to any of claims 8 to 12, characterized m that said drug minimizes the appearance of adverse effects, such as sedative effects .

14. Use according to any of claims 8 to 13, characterized in that said drug is used m combination with another active ingredient selected among antihistamines, lipoxygenase inhibitors, anti^¬ inflammatories, inhibitors of pro-inflammatory cytokine release, leukotriene receptor antagonists, or compounds that control the release of mediators from mast cells, such as leukotrienes, prostaglandins, thromboxane A2 or platelet-activating factor.