Abstract:
An oromucosal formulation containing as an active ingredient a substituted imidazole derivative of formula (I) 
                                 
where Y is —CH 2 — or —CO—, R 1  is halogen or hydroxy, R 2  is H or halogen and R 3  is H or lower alkyl, or an acid addition salt of this imidazole derivative, and a process for its preparation.

Description:
FIELD OF THE INVENTION 
     The present invention relates to an oromucosal formulation comprising as an active ingredient a substituted imidazole derivative of formula (I) 
                                
wherein Y is —CH 2 — or —CO—, R 1  is halogen or hydroxy, R 2  is H or halogen and R 3  is H or lower alkyl, or an acid addition salt thereof.
 
     The invention also relates to a process for preparing the oromucosal formulation in question. 
     BACKGROUND OF THE INVENTION 
     The compounds of the above-mentioned formula (I) are highly selective and long-acting antagonists of α 2 -adrenoceptors. The compounds are especially valuable in the treatment of cognitive disorders. Compounds of formula (I) and their preparation have been described in patent publication EP 0 618 906 B1. Specific examples of such compounds are 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole, i.e. fipamezole, and 4-(5-fluoroindan-2-yl)-1H-imidazole. 
     Although the compounds of formula (I) and their salts have good properties as such, they have disadvantages, when formulated for conventional oral administration, i.e. the normal route for administering said compounds. A problem is that the compounds rather quickly decompose in the gastrointestinal area or other body systems prior to accessing systemic blood flow and the therapeutic target organs. This in turn significantly lowers the effect of the compounds in question. 
     Toxicology studies carried out with dogs (see Example 8) have further suggested that cardiac safety considerations are of importance whereas QT prolongation was observed with high oral doses of fipamezole when the systemic concentration of fipamezole reached about 2000 ng/ml. 
     OBJECT AND SUMMARY OF THE INVENTION 
     One object of the present invention is to provide a formulation for administering compounds of formula (I) safely and efficiently. 
     Another object of the present invention is to provide a process for preparing the formulation. 
     Thus, according to one aspect of this invention concerns an oromucosal formulation comprising as an active ingredient a substituted imidazole derivative of formula (I) 
                                
where Y is —CH 2 — or —CO—, R 1  is halogen or hydroxy, R 2  is H or halogen and R 3  is H or lower alkyl, or an acid addition salt thereof, together with additives conventionally used in oromucosal formulations.
 
     According to another aspect, the invention concerns a process for preparing the oromucosal formulation. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     It has now surprisingly been found that the problems of quick decomposition in the gastrointestinal area and compromised cardiac safety of the compounds of formula (I) can be alleviated by formulating the compounds of formula (I) into oromucosal formulations. Such formulations are effective and easy to handle, and therefore they have an advantage in terms of practical administration to the patient. 
     Suitable additives to be used in the formulation according to the present invention are adjuvants, excipients etc. including solvents, preserving agents, flavouring agents, fillers, gelling agents and mucoadhesive polymers. Preferred solvents are alcohols, especially ethanol, water and mixtures thereof. Preferred preserving agents are lower alkyl parahydroxybenzoates, especially methyl and propyl parahydroxybenzoate, and mixtures thereof. Preferred flavouring agents are aspartame, artificial flavours, such as black currant 502.009, and mixtures thereof. 
     In this context, the oromucosal formulation means any type of formulation administered via oral mucosa. Such formulations include e.g. sprays, gels, mucoadhesive buccal tablets and pastes, sublingual tablets and like. The formulation is preferably in the form of a spray. 
     In this context, the term halogen refers to F, Cl, Br and I, preferably to F and Cl and most preferably to F. 
     In this context, the term lower alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms and most preferably 1 or 2 carbon atoms. 
     In this context, the term an acid addition salt refers to an addition salt of any pharmaceutically acceptable acid, preferably hydrochloric acid. 
     In this context, the term an additive conventionally used in oromucosal formulations refers to any additive known by the person skilled in the art to be applicable for oromucosal formulations. 
     An especially preferred active ingredient is fipamezole (JP-1730, 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole hydrochloride). A formulation containing said preferred active ingredient is prepared according to the invention by mixing and dissolving ethanol (96%), purified water, methylparahydroxybenzoate, propylparahydroxybenzoate and aspartame at room temperature, at +15 to +25° C. Followed by adding and dissolving 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole and artificial flavour, such as black currant 502.009A, at room temperature, at +15 to +25° C. The volume of the mixture is adjusted with purified water, followed by filtering and the desired spray formulation is recovered. 
     The following examples illustrate the invention, but are not intended to restrict the scope of the invention. 
     Example 1 
     Spray Formulation Containing 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole hydrochloride (fipamezole) 
     Fipamezole Oromucosal Spray 
     
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                 Quantity 
                   
               
               
                   
                 Ingredient 
                 per 1 ml 
                 Function 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Fipamezole 
                 15.0 
                 mg 
                 Active 
               
               
                   
                 Methyl 
                 1.8 
                 mg 
                 Preservative 
               
               
                   
                 parahydroxybenzoate 
                   
                   
                   
               
               
                   
                 Propyl 
                 0.2 
                 mg 
                 Preservative 
               
               
                   
                 parahydroxybenzoate 
                   
                   
                   
               
               
                   
                 Aspartame 
                 0.5 
                 mg 
                 Flavouring agent 
               
               
                   
                 Artificial flavour* 
                 0.4 
                 mg 
                 Flavouring agent 
               
               
                   
                 Ethanol (96%) 
                 0.416 
                 ml 
                 Solvent 
               
               
                   
                 Purified water 
                 ad 1.0 
                 ml 
                 Solvent 
               
               
                   
               
               
                 *Artificial flavour, such as black currant 502.009A, for example, but not restricted to. 
               
             
          
         
       
     
     Example 2 
     Spray Formulation Containing 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole hydrochloride (fipamezole) 
     Fipamezole Oromucosal Spray 
     
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                 Quantity 
                   
               
               
                   
                 Ingredient 
                 per 1 ml 
                 Function 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Fipamezole 
                 161.0 
                 mg 
                 Active 
               
               
                   
                 Methyl 
                 1.8 
                 mg 
                 Preservative 
               
               
                   
                 parahydroxybenzoate 
                   
                   
                   
               
               
                   
                 Propyl 
                 0.2 
                 mg 
                 Preservative 
               
               
                   
                 parahydroxybenzoate 
                   
                   
                   
               
               
                   
                 Aspartame 
                 0.5 
                 mg 
                 Flavouring agent 
               
               
                   
                 Artificial flavour* 
                 0.4 
                 mg 
                 Flavouring agent 
               
               
                   
                 Ethanol (96%) 
                 0.416 
                 ml 
                 Solvent 
               
               
                   
                 Purified water 
                 ad 1.0 
                 ml 
                 Solvent 
               
               
                   
               
               
                 *Artificial flavour, such as black currant 502.009A, for example, but not restricted to. 
               
             
          
         
       
     
     Example 3 
     Preparation of a Spray Formulation Containing 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole hydrochloride (fipamezole) 
     416.0 ml of ethanol (96%) was mixed with 450.0 ml of purified water to form a homogenous mixture. 1.80 g of methylparahydroxybenzoate, 0.20 g of propylparahydroxybenzoate and 0.5 g of aspartame were added to the mixture and dissolved at room temperature, at +15 to +25° C. 15.0 g of fipamezole, 0.4 g of black currant flavour were added to the mixture and dissolved at room temperature, at +15 to +25° C. The volume of the mixture was adjusted to 1000.0 ml with purified water. The solution was filtered and the desired spray formulation was recovered. 
     Example 4 
     Preparation of an Oromucosal Gel Formulation Containing 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole hydrochloride (fipamezole) 30 mg 
     Composition 
     
       
         
               
               
             
               
               
               
             
           
               
                   
               
               
                 Ingredient 
                 Amount/single dose 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 Fipamezole 
                  30 mg 
               
               
                 2 
                 Ethanol (96%) 
                 250 mg 
               
               
                 3 
                 Poloxamer 407 
                 200 mg 
               
               
                 4 
                 Liquid flavour (artificial) 
                  0.5 mg 
               
               
                 5 
                 Aspartame (sweetener) 
                  0.5 mg 
               
               
                 6 
                 Purified water 
                 519 mg 
               
               
                   
                 Total of 
                 1000 mg  
               
               
                   
               
             
          
         
       
     
     Method of Preparation 
     Fipamezole (1) and ethanol (96%) (2) are mixed and dissolved to form a solution A. Purified water (6), poloxamer 407 (3), liquid flavour (4), and aspartame (5) are mixed and dissolved to form a solution B. Solution A and solution B are cooled down to approx. +5° C., and mixed together to form a homogenous solution. Oromucosal gel formulation is recovered. 
     Example 5 
     Preparation of a Mucoadhesive Buccal Tablet Formulation Containing 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole hydrochloride fipamezole) 30 mg 
     Composition 
     
       
         
               
               
             
               
               
               
             
           
               
                   
               
               
                 Ingredient 
                 Amount/single dose 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 Fipamezole 
                   30 mg 
               
               
                 2 
                 Carbomer 934P 
                 12.35 mg  
               
               
                 3 
                 Hydroxypropylmethylcellulose 
                 49.4 mg 
               
               
                 4 
                 Flavour (artificial) 
                   4 mg 
               
               
                 5 
                 Aspartame (sweetener) 
                   4 mg 
               
               
                 6 
                 Magnesium stearate 
                 0.25 mg 
               
               
                   
                 Total of 
                  100 mg 
               
               
                   
               
             
          
         
       
     
     Method of Preparation 
     Fipamezole (1), carbomer 934P (2), hydroxypropylmethyl-cellulose (3), flavour (4), aspartame (5), and magnesium stearate (6) are mixed to form a homogenous mixture. The mixture is compressed to tablets of a suitable size. Mucoadhesive buccal tablets are recovered. 
     Example 6 
     Preparation of a Sublingual Tablet Formulation Containing 4-(2-ethyl-5-fluoroindan-2-yl)-1H-imidazole hydrochloride (fipamezole) 30 mg 
     Composition 
     
       
         
               
               
             
               
               
               
             
           
               
                   
               
               
                 Ingredient 
                 Amount/single dose 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 Fipamezole 
                  30 mg 
               
               
                 2 
                 Lactose monohydrate 
                  30 mg 
               
               
                 3 
                 Povidone 
                 2.4 mg 
               
               
                 4 
                 Microcrystalline cellulose 
                 10.8 mg  
               
               
                 5 
                 Flavour 
                 3.2 mg 
               
               
                 6 
                 Aspartame (sweetener) 
                 3.2 mg 
               
               
                 7 
                 Magnesium stearate 
                 0.4 mg 
               
               
                   
                 Total of 
                  80 mg 
               
               
                   
               
             
          
         
       
     
     Method of Preparation 
     Fipamezole (1), lactose monohydrate (2), flavour (5), and aspartame (6) are mixed to form a homogenous mixture. The mixture is granulated with 10% aqueous solution of povidone (3). Granules are formed in either high-shear or low-shear mixer. Granulated mixture is let to dry. Dry, granulated mixture is passed through a screen to obtain freely flowing granulate. Microcrystalline cellulose (4) and magnesium stearate (7) are mixed with the granulate. The final blend is compressed to tablets of a suitable size. Sublingual tablets are recovered. 
     Example 7 
     Oromucosal Delivery of Fipamezole 
     Plasma levels of fipamezole were studied in healthy male volunteers after oral administration of the drug as a solution. Blood samples for pharmcokinetic evaluation were collected for 24 hours after the drug administration. The concentration of fipamezole in plasma was measured with HPLC-MS/MS, and the pharmacokinetic parameters were calculated. The pharmacokinetics of fipamezole was evaluated with TopFit 2.0 pharmacokinetic program. The C max  and t max  values were read from the concentration vs. time curves, and the apparent elimination phase half-lives from the terminal part of the semilogarithmic concentration vs. time curve (see  FIG. 1 ). AUC values were calculated both to infinity and up to the last collection time with quantifiable fipamezole concentration. The results are given in Table 1. 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Mean (SD) pharmacokinetic parameters of fipamezole at the dose 
               
               
                 level of 30 mg. t max  values are given as median and range. 
               
             
          
           
               
                   
                 30-mg 
                   
                   
                   
                 AUC 0-inf   
               
               
                   
                 dosing 
                 C max  (ng/ml) 
                 t max  (h)a 
                 t 1/2el (h)   
                 (ng * h/ml) 
               
               
                   
               
             
          
           
               
                   
                 Oral 
                 1.59 
                 1.0 
                 3.10 
                 7.65 
               
               
                   
                   
                 (0.38) 
                 (0.75-2.0) 
                 (2.23) 
                 (2.99) 
               
               
                   
                 Oromucosal, 
                 31.74 
                  0.85 
                 3.10 
                 115.6 
               
               
                   
                 tablet 
                 (13.50) 
                 (0.43) 
                 (1.00) 
                 (41.10) 
               
               
                   
                 Oromucosal, 
                 49.2 
                 0.7 
                 2.10 
                 157.1 
               
               
                   
                 spray 
                 (11.0) 
                 (0.5-1.0) 
                 (0.20) 
                 (24.7) 
               
               
                   
               
               
                 C max , maximal drug concentration in serum; 
               
               
                 t max , time of maximal drug concentration in serum; 
               
               
                 t 1/2el , apparent elimination phase half-life; 
               
               
                 AUC 0-inf , area under the drug concentration in serum vs. time curve from time 0 to infinity. 
               
             
          
         
       
     
     Mean plasma concentration time plot following single dose administration of 30 mg fipamezole via an oral, oromucosal spray and an oromucosal tablet on a semilogarithmic scale is shown in  FIG. 1 . 
     Example 8 
     Cardiac Safety 
     Cardiac safety was studied in dogs in a 30-day dog toxicology study using oral dosing and dog toxicology studies using buccal dosing. 
     In the 30-day dog toxicology study fipamezole was administered orally at doses of 1, 5, 10 and 15 mg/kg/day for 30 days, resulting in maximum systemic fipamezole concentrations of about 200, 1000, 2000 and 3300 ng/ml, respectively. These in vivo results in the dog suggested that QT prolongation was observed when the systemic concentration of fipamezole reached about 2000 ng/ml. 
     In another toxicology study four male dogs were given fipamezole in buccal spray doses of 1, 5 and 10 mg/kg in a sequential dosing regimen with 5 to 15 days between doses. Blood pressure (systolic, diastolic and mean), heart rate and ECGs were monitored before and up to 12 hours after dosing. At 30 minutes after dosing with 5 and 10 mg/kg significant transient increases in absolute values for blood pressure and heart rate were observed. No ECG changes (P wave amplitude, P wave duration, P-Q interval, QRS interval or Q-T [Q-Tcv, QTc] interval) were apparent after fipamezole dosing at each dose level. 
     Yet another toxicology study using buccal delivery to dogs at dose levels of 1, 5 and 10 mg/kg/day for up to 4 weeks showed no apparent changes in ECG. Maximum systemic concentrations of fipamezole after dosing on the first day of this study were about 800, 2000 and 3300 ng/ml.