Patent Publication Number: US-11382901-B2

Title: Tropicamide-based ophthalmic formulations

Description:
This application is a National Stage Application of PCT/IB2018/054546, filed 20 Jun. 2018, which claims the benefit of Ser. No. 102017000069664, filed 22 Jun. 2017 in Italy, and which applications are incorporated herein by reference. To the extent appropriate, a claim of priority is made to each of the above-disclosed applications. 
     The present invention relates to an ophthalmic composition comprising tropicamide, at least one cyclodextrin at concentrations of less than 2.5%, at least one surfactant at concentrations of less than 2.5%. Said composition is physically stable at neutral pH. 
     BACKGROUND ART 
     Tropicamide is a synthesis molecule with mydriatic and cycloplegic action used in ophthalmic formulations at concentrations typically from 0.5% to 1%. The main application is for diagnostic purposes, for the inspection of the fundus and other ocular structures. Therapeutic indications have been reported for cases of conjunctivitis, keratitis, iritis, iridocyclitis and uveitis. 
     Tropicamide (formula I) 
     
       
         
         
             
             
         
       
     
     is a weak base and the water solubility thereof is rather low and may decrease further in the presence of excipients such as buffers, osmotizing agents, preservatives, generally present in a formulation (Saettone et al., Int J Pharm 1988, 43; 67-76). The water-solubility of Tropicamide increases as pH decreases. 1% tropicamide solutions need a pH of about 5. 
     The physiological pH of the tear is variable in the range from 6.5 to 7.6, with an average value of 7.0±0.20 (Abelson M B, Arch Ophthalmol 1981, 99; 301). The administration of eye drops with a pH outside this range are poorly tolerated by the human eye, which reacts by inducing lacrimation to restore physiological pH. Induced lacrimation has, as an inevitable consequence, the lowering of the bioavailability of the active ingredient (Lee V H L et al., J Ocular Pharmacol 1986, 2; 67-108). 
     The currently available Tropicamide eye drops are formulated at acidic pHs from 4.0 to 5.8 (Lik Thai Lim et al., Int J Ophtalmol 2014, 7; 1067-1068) and should be administered in repeated doses, in some cases even 3-times at a distance of 5′. Such a type of administration causes a prolonged discomfort to the patient, since the eye irritated by acidic solutions takes from 20 to 40 minutes to restore its physiological pH (William H et al., British J Ophthalmol, 1984, 68; 549-552). 
     Cappello et al. (Int J Pharmaceutics 2001, 213; 75-81) describe the obtainment of a physically stable 1% Tropicamide solution at pH 7.4 in 0.02 M phosphate buffer: The physical stability is obtained by adding 4% hydroxypropyl-β-cyclodextrin (HP-β-CD). Although the concentration of HP-β-CD is not high, valid reasons including cost, toxicity and even bioavailability induce the same authors to reduce the HP-13-CD content. Cappello et al. report, in fact, that the concentration of HP-β-CD can be reduced from 4% to 0.9% with the association with 0.1% hydroxypropyl methylcellulose, heating the formulation in autoclave at 120° C. for 20 minutes, and then stirring the solution for 6 days at room temperature. It is apparent that the procedure, especially for the high temperatures required and the timing, is not industrially scalable. 
     Carmignani C et al. (Drug Development Industrial Pharmacy 2002, 28; 101-105, 2002) obtain a 1% TRP solution with surfactants. Four 1% TRP solutions are described, containing tyloxapol (TY), pluronic P85 (PL), Cremophor (CR) and associations of CR and PL, respectively. Of these 4 solutions, only the first 2 are formulated at neutral pH (7.0-7.2), while for the other two the pH does not exceed pH 6.2, therefore below the tolerability limit of the eye. With regard to surfactants, for TY there is a considerable in vitro toxicity on RAW 264.7 cells (murine macrophage-like) and on NIH/3T3 cells (murine fibroblasts). In general, TY toxicity is reduced by associating it with dipalmitoylphosphatidylcholine, which limits the interaction of TY with the cell membrane (Jung-Hua Steven Kuo Pharm Res 2006, 23). For PL, polymeric surfactants consisting of polyoxyethylene/polyoxypropylene co-polymer blocks, in varying proportions and of different molecular weight, the ophthalmological use is wide. 5,252,246 describes a relatively safe use of pluronic 85 up to 10%. In Carmignani et al., pluronic P85 is instead used at concentrations higher than 15%, which concentration is above the safety limits. Such a high percentage, 15% PL, required to solubilize 1% TRP at pH 7.2, is therefore poorly tolerated even at neutral pH. 
     The need to have an aqueous formulation based on Tropicamide with a neutral pH, well tolerated by the eye so as to obtain a longer pre-corneal residence time and therefore a greater bioavailability of the drug compared to that observed with the currently available compositions, is therefore strongly felt. 
    
    
     DESCRIPTION OF THE INVENTION 
     The present invention relates to a neutral pH composition comprising TRP from 0.1% to 1.2%, preferably from 0.2 to 1%, even more preferably from 0.4 to 0.8%, at least one cyclodextrin at concentrations lower than 2.5%, and at least one surfactant, at concentrations lower than 2.5%. 
     Said composition, formulated as described in the present invention, proved to be well tolerated when administered to the eye, as well as being physically stable for 24 months. 
     The following examples demonstrate how the two excipients cyclodextrin and surfactant, used in combination, surprisingly show a synergistic solubilizing effect such as to allow the reduction of the concentration of the volumes required when they are used individually. This means that the total content given by the sum of cyclodextrin and surfactant, required to keep tropicamide in solution at neutral pH, is lower than the required content of cyclodextrin or surfactant used individually. 
     The advantageous effects observed with the formulation according to the present invention are achieved by the synergy between cyclodextrin and a surfactant, where said surfactant consists of a compound other than a cyclodextrin. 
     The composition according to the present invention is formulated at room temperature, without requiring long times for the dissolution of tropicamide. 
     Said cyclodextrins are preferably γ- or β-cyclodextrins, even more preferably HP-β-CD. The concentration of HP-β-CD is from 0.5 to 2.5%, preferably from 0.8 to 2.0%. 
     Said surfactants are selected from the group comprising quaternary ammonium salts, hydrophilic non-ionic surfactants such as polyethylene glycol (15)-hydroxystearate (Solutol HS 15 SOL), polyethylene glycol (40). Preferably, said surfactant is polyethylene glycol (15)-hydroxystearate and is at a concentration ranging from 0.5 to 2.5%, preferably from 0.8 to 2.0%. 
     In order to obtain the neutral pH, the composition comprises a phosphate, citrate or borate buffer in a pH range from 6.5 to 7.4 and preferably from pH 6.8 to 7.2. For pH correction, strong acidic solutions or strong bases may be used. 
     Said composition, in one embodiment, comprises osmotizing agents preferably selected from the group comprising glycerol, sorbitol, mannitol, trehalose and sodium chloride. 
     Said composition, in one embodiment, also comprises viscous polymers preferably selected from the group comprising Carbopol, polyvinyl alcohol, hydroxypropyl cellulose, HP-Guar, dextran and hyaluronic acid, preferably sodium hyaluronate (HA) at concentrations from 0.01% to 0.25%, or from 0.08 to 0.2%. 
     Said composition, in one embodiment, also comprises preservatives, preferably selected from the group comprising ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride or polyhexanide (PHMB). 
     The composition according to the present invention is exemplified in the following examples. 
     Examples 1-3: Formulations of TRP+HP-β-CD+SOL at Different TRP Concentration 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                 Example 1  
                 Example 2  
                 Example 3  
               
               
                 Ingredients 
                 % w/w 
                 % w/w 
                 % w/w 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 TRP 
                 0.5 
                 1.0 
                 0.2 
               
               
                 HP-β-CD 
                 1.0 
                 2.0 
                 0.5 
               
               
                 SOL 
                 1.5 
                 2.5 
                 0.8 
               
               
                 Sodium 
                 0.2 
                 0.2 
                 0.2 
               
               
                 phosphate 
                   
                   
                   
               
               
                 dibasic 
                   
                   
                   
               
               
                 dodecahydrate 
                   
                   
                   
               
               
                 Sodium 
                 0.065 
                 0.065 
                 0.065 
               
               
                 phosphate 
                   
                   
                   
               
               
                 monobasic 
                   
                   
                   
               
               
                 bihydrate 
                   
                   
                   
               
               
                 Glycerol 
                 0.9 
                 0.9 
                 0.9 
               
               
                 Mannitol 
                 2.0 
                 2.0 
                 2.0 
               
               
                 Sodium 
                 0.15 
                 0.15 
                 0.15 
               
               
                 Hyaluronate 
                   
                   
                   
               
               
                 EDTA-Na 2 *2H 2 O 
                 0.025 
                 0.025 
                 0.025 
               
               
                 PHMB 
                 0.001 
                 0.001 
                 0.001 
               
               
                 Purified 
                 up to 100 g 
                 up to 100 g 
                 up to 100 g 
               
               
                 water 
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     Examples 4-6: 1% TRP Formulations Comprising Me-β-CD, Sb-β-CD or γCD 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                 Example 4  
                 Example 5  
                 Example 6  
               
               
                 Ingredients 
                 % w/w 
                 % w/w 
                 % w/w 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 TRP 
                 1.0 
                 1.0 
                 1.0 
               
               
                 Methyl-β- 
                 1.5 
                   
                   
               
               
                 cyclodextrin 
                   
                   
                   
               
               
                 (Me-β-CD) 
                   
                   
                   
               
               
                 Sulphobutylether- 
                   
                 2.0 
                   
               
               
                 cyclodextrin (Sb- 
                   
                   
                   
               
               
                 β-CD) 
                   
                   
                   
               
               
                 γ-Cyclodextrin 
                   
                   
                 2.5 
               
               
                 SOL 
                 2.5 
                 2.5 
                 2.5 
               
               
                 Sodium phosphate 
                 0.2 
                 0.2 
                 0.2 
               
               
                 dibasic 
                   
                   
                   
               
               
                 dodecahydrate 
                   
                   
                   
               
               
                 Sodium phosphate 
                 0.065 
                 0.065 
                 0.065 
               
               
                 monobasic 
                   
                   
                   
               
               
                 bihydrate 
                   
                   
                   
               
               
                 Glycerol 
                 0.9 
                 0.9 
                 0.9 
               
               
                 Mannitol 
                 2.0 
                 2.0 
                 2.0 
               
               
                 Sodium 
                 0.15 
                 0.15 
                 0.15 
               
               
                 Hyaluronate 
                   
                   
                   
               
               
                 EDTA-Na 2 *2H 2 O 
                 0.025 
                 0.025 
                 0.025 
               
               
                 PHMB 
                 0.001 
                 0.001 
                 0.001 
               
               
                 Purified water 
                 up to 100 g 
                 up to 100 g 
                 up to 100 g 
               
               
                   
               
            
           
         
       
     
     Examples 7-9: 1% TRP Formulations Comprising Cremophor, Tween 80, Pluronic 85 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                 Example 7  
                 Example 8  
                 Example 9  
               
               
                 Ingredients 
                 % w/w 
                 % w/w 
                 % w/w 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 TRP 
                 1.0 
                 1.0 
                 1.0 
               
               
                 HP-β-CD 
                 2.0 
                 2.0 
                 2.5 
               
               
                 polyethoxylated 
                 2.5 
                   
                   
               
               
                 castor oil 
                   
                   
                   
               
               
                 (Cremophor) 
                   
                   
                   
               
               
                 Tween 80 
                   
                 2.0 
                   
               
               
                 Pluronic P85 
                   
                   
                 2.5 
               
               
                 Sodium 
                 0.2 
                 0.2 
                 0.2 
               
               
                 phosphate 
                   
                   
                   
               
               
                 dibasic 
                   
                   
                   
               
               
                 dodecahydrate 
                   
                   
                   
               
               
                 Sodium 
                 0.065 
                 0.065 
                 0.065 
               
               
                 phosphate 
                   
                   
                   
               
               
                 monobasic 
                   
                   
                   
               
               
                 bihydrate 
                   
                   
                   
               
               
                 Glycerol 
                 0.9 
                 0.9 
                 0.9 
               
               
                 Mannitol 
                 2.0 
                 2.0 
                 2.0 
               
               
                 Sodium 
                 0.15 
                 0.15 
                 0.15 
               
               
                 Hyaluronate 
                   
                   
                   
               
               
                 EDTA-Na 2 *2H 2 O 
                 0.025 
                 0.025 
                 0.025 
               
               
                 PHMB 
                 0.001 
                 0.001 
                 0.001 
               
               
                 Purified water 
                 up to 100 g 
                 up to 100 g 
                 up to 100 g 
               
               
                   
               
            
           
         
       
     
     Examples 10-14: 1% TRP Formulations Comprising Thickening Agents 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                   
                 Example 
                 Example 
                 Example 
                 Example 
                 Example 
               
               
                   
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 Ingredients 
                 % w/w 
                 % w/w 
                 % w/w 
                 % w/w 
                 % w/w 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 TRP 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
               
               
                 HP-β-CD 
                 2.0 
                 2.0 
                 2.0 
                 2.0 
                 2.0 
               
               
                 SOL 
                 2.5 
                 2.5 
                 2.5 
                 2.5 
                 2.5 
               
               
                 Sodium 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
               
               
                 phosphate 
                   
                   
                   
                   
                   
               
               
                 dibasic 
                   
                   
                   
                   
                   
               
               
                 dodecahydrate 
                   
                   
                   
                   
                   
               
               
                 Sodium 
                 0.065 
                 0.065 
                 0.065 
                 0.065 
                 0.065 
               
               
                 phosphate 
                   
                   
                   
                   
                   
               
               
                 monobasic 
                   
                   
                   
                   
                   
               
               
                 bihydrate 
                   
                   
                   
                   
                   
               
               
                 Glycerol 
                 0.9 
                 0.9 
                 0.9 
                 0.9 
                 0.9 
               
               
                 Mannitol 
                 2.0 
                 2.0 
                 2.0 
                 2.0 
                 2.0 
               
               
                 Hydroxypropyl 
                 0.4 
                   
                   
                   
                   
               
               
                 methylcellulose 
                   
                   
                   
                   
                   
               
               
                 Carbopol 
                   
                 0.2 
                   
                   
                   
               
               
                 Polyvinyl 
                   
                   
                 0.5 
                   
                   
               
               
                 alcohol 
                   
                   
                   
                   
                   
               
               
                 HP-Guar 
                   
                   
                   
                 1.0 
                   
               
               
                 Dextran 
                   
                   
                   
                   
                 5.0 
               
               
                 EDTA- 
                 0.025 
                 0.025 
                 0.025 
                 0.025 
                 0.025 
               
               
                 Na 2 *2H 2 O 
                   
                   
                   
                   
                   
               
               
                 PHMB 
                 0.001 
                 0.001 
                 0.001 
                 0.001 
                 0.001 
               
               
                 Purified water 
                 up to  
                 up to 
                 up to 
                 up to  
                 up to 
               
               
                   
                 100 g 
                 100 g 
                 100 g 
                 100 g 
                 100 g 
               
               
                   
               
            
           
         
       
     
     Examples 15-19 (Comparative): Formulations Similar to the Formulations of Examples 10-14 but which DO NOT Comprise Cyclodextrins 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                   
                 Example 
                 Example 
                 Example 
                 Example 
                 Example 
               
               
                   
                 15 
                 16 
                 17 
                 18 
                 19 
               
               
                 Ingredients 
                 % w/w 
                 % w/w 
                 % w/w 
                 % w/w 
                 % w/w 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 TRP 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
               
               
                 SOL 
                 2.5 
                 2.5 
                 2.5 
                 2.5 
                 2.5 
               
               
                 Sodium 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
               
               
                 phosphate 
                   
                   
                   
                   
                   
               
               
                 dibasic 
                   
                   
                   
                   
                   
               
               
                 dodecahydrate 
                   
                   
                   
                   
                   
               
               
                 Sodium 
                 0.065 
                 0.065 
                 0.065 
                 0.065 
                 0.065 
               
               
                 phosphate 
                   
                   
                   
                   
                   
               
               
                 monobasic 
                   
                   
                   
                   
                   
               
               
                 bihydrate 
                   
                   
                   
                   
                   
               
               
                 Glycerol 
                 0.9 
                 0.9 
                 0.9 
                 0.9 
                 0.9 
               
               
                 Mannitol 
                 2.0 
                 2.0 
                 2.0 
                 2.0 
                 2.0 
               
               
                 Hydroxypropyl 
                 0.4 
                   
                   
                   
                   
               
               
                 methylcellulose 
                   
                   
                   
                   
                   
               
               
                 Carbopol 
                   
                 0.2 
                   
                   
                   
               
               
                 Polyvinyl 
                   
                   
                 0.5 
                   
                   
               
               
                 alcohol 
                   
                   
                   
                   
                   
               
               
                 HP-Guar 
                   
                   
                   
                 1.0 
                   
               
               
                 Dextran 
                   
                   
                   
                   
                 5.0 
               
               
                 EDTA- 
                 0.025 
                 0.025 
                 0.025 
                 0.025 
                 0.025 
               
               
                 Na 2 *2H 2 O 
                   
                   
                   
                   
                   
               
               
                 PHMB 
                 0.001 
                 0.001 
                 0.001 
                 0.001 
                 0.001 
               
               
                 Purified water 
                 up to  
                 up to 
                 up to 
                 up to  
                 up to  
               
               
                   
                 100 g 
                 100 g 
                 100 g 
                 100 g 
                 100 g 
               
               
                   
               
            
           
         
       
     
     Examples 20-22 (Comparative): Formulations Similar to the Formulations of Examples 7-9 but which DO NOT Comprise a Surfactant 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                 Example 20  
                 Example 21  
                 Example 22  
               
               
                 Ingredients 
                 % w/w 
                 % w/w 
                 % w/w 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 TRP 
                 1.0 
                 1.0 
                 1.0 
               
               
                 HP-β-CD 
                 2.0 
                 2.0 
                 2.5 
               
               
                 Sodium 
                 0.2 
                 0.2 
                 0.2 
               
               
                 phosphate 
                   
                   
                   
               
               
                 dibasic 
                   
                   
                   
               
               
                 dodecahydrate 
                   
                   
                   
               
               
                 Sodium 
                 0.065 
                 0.065 
                 0.065 
               
               
                 phosphate 
                   
                   
                   
               
               
                 monobasic 
                   
                   
                   
               
               
                 bihydrate 
                   
                   
                   
               
               
                 Glycerol 
                 0.9 
                 0.9 
                 0.9 
               
               
                 Mannitol 
                 2.0 
                 2.0 
                 2.0 
               
               
                 Sodium 
                 0.15 
                 0.15 
                 0.15 
               
               
                 Hyaluronate 
                   
                   
                   
               
               
                 EDTA-Na 2 *2H 2 O 
                 0.025 
                 0.025 
                 0.025 
               
               
                 PHMB 
                 0.001 
                 0.001 
                 0.001 
               
               
                 Purified 
                 up to 100 g 
                 up to 100 g 
                 up to 100 g 
               
               
                 water 
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     Examples 23-24 (Comparative): Formulations Similar to the Formulations of Examples 1-2 but which DO NOT Comprise a Surfactant 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Ingredients 
                 Example 23 % w/w 
                 Example 24 % w/w 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 TRP 
                 0.5 
                 1.0 
               
               
                 HP-β-CD 
                 1.0 
                 2.0 
               
               
                 Sodium phosphate 
                 0.2 
                 0.2 
               
               
                 dibasic 
                   
                   
               
               
                 dodecahydrate 
                   
                   
               
               
                 Sodium phosphate 
                 0.065 
                 0.065 
               
               
                 monobasic bihydrate 
                   
                   
               
               
                 Glycerol 
                 0.9 
                 0.9 
               
               
                 Mannitol 
                 2.0 
                 2.0 
               
               
                 Sodium Hyaluronate 
                 0.15 
                 0.15 
               
               
                 EDTA-Na 2 *2H 2 O 
                 0.025 
                 0.025 
               
               
                 PHMB 
                 0.001 
                 0.001 
               
               
                 Purified water 
                 up to 100 g 
                 up to 100 g 
               
               
                   
               
            
           
         
       
     
     Below are given the stability studies related to the formulations of Examples 1 to 24. 
     It should be noted that, as for the comparative Examples 15 to 24, the same studies could not be conducted because the TRP in said formulations did not go into solution when operating at 25° C. or, within one month from preparation, the formation of a precipitate occurred. 
     Conversely, for the formulations comprising the components according to the present invention, the following data were obtained. 
     Stability of the formulations of Examples 1-5 at a temperature of 25±2° C. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 Example 
                 Example 
                 Example 
                 Example 
                 Example 
               
               
                   
                   
                   
                 1 
                 2 
                 3 
                 4 
                 5 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Months 
                   
                 % TRP 
                 0.5 
                 1.0 
                 0.2 
                 1.0 
                 1.0 
               
               
                   
                 Initial 
                 pH 
                 7.0 
                 7.0 
                 7.1 
                 7.0 
                 7.0 
               
               
                   
                 value 
                 mOsm/ 
                 285 
                 290 
                 283 
                 268 
                 288 
               
               
                   
                   
                 kg 
                   
                   
                   
                   
                   
               
               
                   
                  3 
                 % TRP 
                 0.5 
                 1.0 
                 0.2 
                 1.0 
                 1.0 
               
               
                   
                   
                 pH 
                 7.0 
                 7.0 
                 7.1 
                 7.0 
                 7.0 
               
               
                   
                   
                 mOsm/ 
                 287 
                 292 
                 285 
                 291 
                 290 
               
               
                   
                   
                 kg 
                   
                   
                   
                   
                   
               
               
                   
                 12 
                 % TRP 
                 0.5 
                 1.0 
                 0.2 
                 1.0 
                 1.0 
               
               
                   
                   
                 pH 
                 7.0 
                 6.9 
                 7.1 
                 7.0 
                 6.9 
               
               
                   
                   
                 mOsm/ 
                 288 
                 295 
                 288 
                 295 
                 294 
               
               
                   
                   
                 kg 
                   
                   
                   
                   
                   
               
               
                   
                 18 
                 % TRP 
                 0.5 
                 1.0 
                 0.2 
                 1.0 
                 1.0 
               
               
                   
                   
                 pH 
                 7.0 
                 6.9 
                 7.0 
                 6.9 
                 6.9 
               
               
                   
                   
                 mOsm/ 
                 292 
                 298 
                 293 
                 298 
                 298 
               
               
                   
                   
                 kg 
                   
                   
                   
                   
                   
               
               
                   
                 24 
                 % TRP 
                 0.5 
                 1.0 
                 0.2 
                 1.0 
                 1.0 
               
               
                   
                   
                 pH 
                 6.9 
                 6.8 
                 7.0 
                 6.9 
                 6.8 
               
               
                   
                   
                 mOsm/ 
                 295 
                 301 
                 295 
                 302 
                 300 
               
               
                   
                   
                 kg 
               
               
                   
               
            
           
         
       
     
     Stability of the formulations of Examples 6-10 at a temperature of 25±2° C. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 Example 
                 Example 
                 Example 
                 Example 
                 Example 
               
               
                   
                   
                   
                 6 
                 7 
                 8 
                 9 
                 10 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Months 
                 Initial 
                 % TRP 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
               
               
                   
                 value 
                 pH 
                 7.0 
                 7.1 
                 7.1 
                 7.0 
                 7.1 
               
               
                   
                   
                 mOsm/ 
                 290 
                 289 
                 290 
                 288 
                 291 
               
               
                   
                   
                 kg 
                   
                   
                   
                   
                   
               
               
                   
                  3 
                 % TRP 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
               
               
                   
                   
                 pH 
                 7.0 
                 7.1 
                 7.0 
                 7.0 
                 7.1 
               
               
                   
                   
                 mOsm/ 
                 293 
                 292 
                 293 
                 290 
                 291 
               
               
                   
                   
                 kg 
                   
                   
                   
                   
                   
               
               
                   
                 12 
                 % TRP 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
               
               
                   
                   
                 pH 
                 6.9 
                 7.1 
                 7.0 
                 6.9 
                 7.0 
               
               
                   
                   
                 mOsm/ 
                 296 
                 295 
                 296 
                 293 
                 293 
               
               
                   
                   
                 kg 
                   
                   
                   
                   
                   
               
               
                   
                 18 
                 % TRP 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
               
               
                   
                   
                 pH 
                 6.9 
                 7.1 
                 7.0 
                 6.9 
                 7.0 
               
               
                   
                   
                 mOsm/ 
                 298 
                 302 
                 300 
                 294 
                 295 
               
               
                   
                   
                 kg 
                   
                   
                   
                   
                   
               
               
                   
                 24 
                 % TRP 
                 0.9 
                 1.0 
                 0.9 
                 1.0 
                 1.0 
               
               
                   
                   
                 pH 
                 6.8 
                 6.9 
                 6.9 
                 6.9 
                 6.9 
               
               
                   
                   
                 mOsm/ 
                 301 
                 303 
                 302 
                 298 
                 301 
               
               
                   
                   
                 kg 
               
               
                   
               
            
           
         
       
     
     The compositions of Examples 11-14 comprise TRP, HP-β-CD and Solutol at the same concentrations included in the composition according to Example 2 and Example 10, the difference being the presence of thickening agents. The stability data obtained are superimposable with the data obtained in the absence of thickening agents, confirming that the stabilization effect is obtained due to the synergistic effect of cyclodextrins and surfactant and it is not affected by the addition of thickening agents.