Stabilized galenic formulations comprising an acid labile benzimidazole compound and its preparation
FIELD OF THE INVENTION 
     The present invention is related to new stable pharmaceutical preparations for oral administration containing a 2[(2-pyridyl)methylsulphinyl]-benzimidazole derivative (hereinafter referred to as &#34;benzimidazole compound&#34;) of formula I: ##STR1## wherein R 1  is hydrogen, methoxy or difluoromethoxy, R 2  is methyl or methoxy, R 3  is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy, R 4  is hydrogen or methyl. 
     The invention also relates to a method for the manufacture of such preparations and to a method for the treatment of gastrointestinal diseases. 
     BACKGROUND OF THE INVENTION 
     The above benzimidazole compounds are very effective drugs for the treatment of gastric and duodenal ulcers, gastroesophageal reflux disease, severe erosive esophagitis, Zollinger-Ellison syndrome and H pylori eradication. However, it is well known that these compounds have poor stability. In the solid state they are susceptible to heat, moisture and light, and in aqueous solution or suspension their stability decreases with decreasing pH. The degradation of these compounds is catalyzed by acidic reacting compounds. 
     Pharmaceutical preparations containing acid-labile compounds have to be subcoated in order to avoid a reaction between the active ingredient and the outer acidic enteric coating which reaction--if occurring--would result in degradation, destabilization and consequently discoloration of the active ingredient. 
     The use of a barrier layer to protect the pharmaceutical from degradation caused by an enteric coating is well known from the prior art. Nevertheless, it is not possible to use conventional enteric coatings in a conventional way for acid labile benzimidazole compounds since decomposition takes place and the preparations become discolored and lose the active ingredient content with time. Prior art partially avoids the above mentioned stability problem by including an alkaline salt form of the benzimidazole compound or incorporating an alkaline reacting compound into an enteric coated preparation (U.S. Pat. No. 4,786,505, U.S. Pat. No. 5,232,706, EP 237200, EP 124495), the alkaline reacting compound being present within or on the surface of the nucleus together with the benzimidazole compound. Also the alkaline reacting compound is being used in the composition of a second isolation layer to ensure stability of these forms. Thus, the association of an alkaline substance to the neutral form of the benzimidazole compound is taught in order to improve the stability of the active compound, especially for solid dosage forms, and enteric coating is recommended. Nevertheless, a superior stability of the preparations would be required to ensure the stability of the drug for long term storage. 
     OUTLINE OF THE INVENTION 
     According to the present invention high stability solid preparations containing a benzimidazole compound of formula I are obtained. The new galenic formulations do not contain alkaline reacting compounds. It has been found that it is not necessary to create an alkaline environment into the enteric coated preparation. The obtained new preparations have a significantly enhanced stability for long-term storage, much higher than the known preparations, avoid discoloration and loss of purity and, thus are more suitable for pharmaceutical use. 
     The new preparation is characterized in that to an inert sugar/starch spherical core, a first layer is applied containing a mixture of the benzimidazole compound of formula I as active ingredient, a water soluble inert polymer and non-alkaline reacting pharmaceutical acceptable excipients, followed by a second isolation layer formed by water soluble polymers and compatible excipients. Finally a third layer consisting of an enteric coating is applied. The core, the process conditions and the excipients have been selected in order to obtain the required coating efficiency for each layer. 
     The resulting new preparation is resistant to dissolution in acid media being stable for passage through the gastric juice, and dissolves rapidly in a neutral to alkaline media, the conditions in the proximal part of the small intestine. In fact, the acid resistance, tested as per US Pharmacopoeia, demonstrated that after 2 hours the total amount of the benzimidazole remained intact and that upon changing the pH to 6.8, after 30 minutes all the benzimidazole was dissolved (tested as per US Pharmacopoeia). 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In a fluidized bed apparatus, uniform spherical inert cores (composition as per US Pharmacopoeia) are coated with a first layer consisting of the acid labile benzimidazole compound, an inert water soluble polymer such as hydroxypropylmethylcellulose or hydroxypropylcellulose, and talc. The second layer consists of an inert water soluble polymer such as hydroxypropylmethylcellulose or hydroxpropylcellulose, talc and a pigment such as titanium dioxide. The third and enteric coating layer consists of an enteric coating polymer such as co-polymerized methacrylic acid/methacrylic acid methyl esters, a plasticizer such as triethylcitrate or similar plasticizers, and talc. 
     The layers are applied by conventional fluidized bed coating techniques using aqueous solutions or dispersions. 
     The active ingredients can be administered in the same dosages and according to the same protocol as the corresponding already marketed commercial dosage forms. 
     For oral administration, the final dosage may take the form of capsules containing the pellets, or pellets compressed into a tablet. 
     The dose as the benzimidazole compound lies within the range of about 1 mg to 100 mg/kg/day, adjusted to individual patients needs and for as long as clinically indicated. 
     The invention is described in detail in the following examples: 
     EXAMPLE 1 
     In 3440 g of deionized water 436 g of Omeprazole (I; R 1  ═-OCH 3 , R 2  ═CH 3 , R 3  ═-OCH 3 , R 4  ═CH 3 ), 444 g of hydroxypropylmethylcellulose and 118 g of talc are dispersed. 
     3010 g of inert uniform sugar/starch spheres (composition according to US Pharmacopoeia) are introduced into a fluidized bed apparatus and the previous obtained dispersion is sprayed on the spheres. After spraying, the spheres are dried before applying the second layer. 
     In 2365 g of deionized water, 355 g of hydroxypropylmethylcellulose, 43 g of talc and 43 g of titanium dioxide are dispersed and the resulting aqueous dispersion is sprayed on the spheres obtained in the previous step. After spraying, the spheres are dried before applying the third enteric coating layer. 
     In 1890 g of deionized water, 1950 g of methacrylic acid copolymer (US Pharmacopoeia, type C aqueous dispersion), 98 g of triethylcitrate and 98 g of talc are dispersed, and the resulting aqueous dispersion is sprayed on the spheres obtained in the previous step. After applying this final enteric coating layer the spheres (pellets) are dried. 
     The pellets thus obtained were stored in closed polyethylene bags within a closed cardboard fibre container and also in closed glass containers and submitted to so called accelerated conditions, that is 40° C. and 75% relative humidity. At the same time pellets obtained from Prilosec® capsules (Merck/Astra trademark) were stored in identical containers and submitted to the same conditions. The results of the test under accelerated conditions are summarized in tables 1, 2 and 3. They demonstrate a superior stability over the already authorized product on the market. 
     
                       TABLE 1                                                     
______________________________________                                    
COLOR OF THE PELLETS                                                      
            AT THE                                                        
            START     1 MONTH    3 MONTHS                                 
______________________________________                                    
Pellets (I) - Fiber                                                       
            A         A          D                                        
container                                                                 
Pellets (I) - Glass                                                       
            A         A          B                                        
container                                                                 
Prilosec - Fiber                                                          
            A         C          F                                        
container                                                                 
Prilosec - Glass                                                          
            A         A          E                                        
container                                                                 
______________________________________                                    
 A: White                                                                 
 B: Pinkish white                                                         
 C: faint brown                                                           
 D: light brown                                                           
 E: brown                                                                 
 F: Deep brown                                                            
 
    
     
                       TABLE 2                                                     
______________________________________                                    
OMEPRAZOLE PURITY*                                                        
            AT THE                                                        
            START     1 MONTH    3 MONTHS                                 
______________________________________                                    
Pellets (I) - Fiber                                                       
            99,5%     98,8%      52%                                      
container                                                                 
Pellets (I) - Glass                                                       
            99,5%     98,7%      97,9%                                    
container                                                                 
Prilosec - Fiber                                                          
            96,1%     85,2%      1%                                       
container                                                                 
Prilosec - Glass                                                          
            96,1%     96,2%      1%                                       
container                                                                 
______________________________________                                    
 *Analyzed as per HPLC, described in Pharmaeuropa, Vol. 4, n° 2,   
 June 1992 and expressed as direct area percentage.                       
 
    
     
                       TABLE 3                                                     
______________________________________                                    
OMEPRAZOLE RECOVERY                                                       
AFTER US DISSOLUTION TEST                                                 
                1 MONTH   3 MONTHS                                        
______________________________________                                    
Pellets (I) - Fiber                                                       
                96,8%     9,2%                                            
container                                                                 
Pellets (I) - Glass                                                       
                99,9%     73,8%                                           
container                                                                 
Prilosec - Fiber                                                          
                21,3%     &lt;&lt;1%                                            
container                                                                 
Prilosec - Glass                                                          
                84,5%     &lt;&lt;1%                                            
container                                                                 
______________________________________                                    
 
    
     EXAMPLE 2 
     In 580 g of deionized water, 75 g of Lansoprazole (I; R 1  ═H, R 2  ═CH 3 , R 3  ═2,2,2-trifluoroethoxy, R 4  ═H), 70 g of hydroxypropylmethylcellulose and 18.5 g of talc are dispersed. 
     490 g of inert uniform sugar/starch spheres are introduced into a fluidized bed apparatus and the previous obtained dispersion is sprayed on the spheres. The process continues in the same manner as in Example 1 spraying the second layer and the third enteric coating layer. These two dispersions have the following composition: 
     Second layer: 350 g of deionized water, 52 g of hydroxypropylmethylcellulose, 7 g of talc and 7 g of titanium dioxide. 
     Enteric coating layer: 280 g of deionized water, 290 g of a USP methacrylic acid copolymer (type C aqueous suspension), 13 g of triethylcitrate and 13 g of talc. 
     The pellets obtained were stable and showed a similar profile as the ones from example 1.