Patent Publication Number: US-4223008-A

Title: Slow release pharmaceutical compositions containing 3-[2-(4-benzamido-1-piperidyl)ethyl]indole, embonate

Description:
This invention relates to slow release pharmaceutical compositions containing an indole derivative. 
     In UK Patent Specification No. 1,218,570 there are described and claimed a class of indole derivatives which have various pharmacological activities, especially action on the cardiovascular system. One of these compounds 3-[2-(4-benzamido-1-piperidyl)ethyl]indole has demonstrated valuable antihypertensive properties in human beings as shown in clinical trials. This compound, which has the international approved name, indoramin, is generally used in the form of its hydrochloride salt. 
     A novel salt, namely the embonic acid salt, has shown potent antihypertensive activity in a standard test. This salt is described and claimed in co-pending U.S. pat. application Ser. No. 38,596 filed the same day. present application in the name of John Leheup Archibald. 
     I have now surprisingly found from standard dissolution tests that the embonate salt of indoramin is particularly useful when employed in formulations where it is desired to achieve slow release of indoramin. 
     In the standard test, the embonate salt of indoramin was found to have an intrinsic dissolution rate different from the hydrochloride salt in solutions at medium pH. However, dissolution rates of embonate and hydrochloride at low pH were roughly equal. The procedure used in testing intrinsic dissolution rate was as follows: 
     Compress 250-500mg raw drug into a smooth cylindrical pellet in a 1.3cm diameter punch and die set, using a suitable laboratory pressure (apply 1-2 tons pressure and attach die to vacuum pump for 10 minutes, compress at 10 tons pressure). Eject the pellet from the die and check that it is free from superficial cracks. 
     Mount pellet centrally on a one inch square section of a microscope slide. Fix with paraffin wax so that the entire upper pellet face is exposed and place centrally at bottom of dissolution flask. 
     At zero time, pour 200ml dissolution medium (0.06NHCl or distilled water, at 37° C.±0.5° C.) into the flask. Check that pellet is undisturbed, start stirrer and timer. 
     Withdraw 10 ml samples of medium every 10 minutes over an hour through a sintered glass filter. Replace the same volume of dissolution medium at 37° C.±0.5° C. after each sampling, to maintain constant volume. 
     Filter each sample through a pre-washed 1.2μ millipore filter in Swinnex holder immediately prior to assay. Assay samples by uv absorbance measurement at 280nm in 1cm quartz cells. Compare with standard solutions (5-30μgml -1 ) and calculate mg indoramin released from each sampling time by reference to the standard graph (concentration plotted against absorbance). 
     Results of testing are shown below: 
     
         ______________________________________                                    
Intrinsic Dissolution Rates in mg per minute per sq cm                    
                Dissolution Medium                                        
Indoramin         0.06 NHCl Distilled                                     
Salt Tested       (pH 1.2)  Water                                         
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Embonate          0.062     0.005                                         
Hydrochloride     0.062     0.424                                         
                  0.062     0.409                                         
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     The results show that the embonate salt and the hydrochloride salt of indoramin have similar dissolution rates at low pH such as found in the stomach. However, at higher pH such as found in the small intestine the rate of dissolution for the embonate salt is much slower than for the hydrochloride and also slower than the value for low pH. 
     Therefore the embonate salt of indoramin can be employed as a means for prolonging the release of indoramin when administered as en enteric coated tablet designed to release the embonate in the small intestine. Such prolonged release dosage forms are preferred in antihypertensive therapy where patients require treatment for a considerable length of time. This is because administration of the drug need not be as frequent as with ordinary release forms and can be reduced, for example, to once a day. As a result patient compliance with long term therapy is generally improved. 
     Accordingly, this invention provides a pharmaceutical composition in tablet form comprising the embonic addition salt of indoramin together with a pharmaceutically acceptable carrier, said tablet having an enteric coating. The carrier may be any suitable solid carrier known in the art. 
     The enteric coating may be any suitable coating known in the art. Examples of film forming substances for use in the enteric coating are hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate and acrylic resin. Plasticizers and lubricants may also be present. The coating may be sprayed onto the tablet core using a suitable solvent carrier. Typically the enteric coating comprises about 3 to about 5% of the tablet weight. 
     The particular dosage will depend on standard pharmaceutical practice. Typical doses for the enteric coated tablet are 200-800 mg indoramin per day, preferably 300-500 mg per day. 
    
    
     The following Example 1 illustrates the preparation of indoramin embonate. Example 2 illustrates the invention. 
     EXAMPLE 1 
     3-[2-(4-Benzamido-1-piperidyl)ethyl-indole, embonate 
     A suspension of 3-[2-(2-(4-benzamido-1-piperidyl)ethyl]-indole (3.47g, 0.01m) and embonic acid (1.94g, 0.05m) is refluxed in 200 mls of absolute ethanol until the solid dissolves. The hot solution is filtered and the solvent evaporated to give a gum. Water is added and the gum scratched until crystallisation occurs (5.4g) m.p. 175°-177° C. 
     Found: C, 74.08%; H, 6.24%; N, 7.55% (C 22  H 25  N 3  O) 2 .C 23  H 10  O 6  requires C, 74.29%; H, 6.14%; N, 7.76%. 
     EXAMPLE 2 
     Enteric Coated Indoramin Embonate Tablets 
     Cores for enteric coated tablets are made to the following two formulations: 
     
         ______________________________________                                    
              1         2                                                 
______________________________________                                    
Indoramin Embonate                                                        
                77.95 (50)  155.89 (100)                                  
Amberlite IRP 88                                                          
                7.0         14.0                                          
Avicel pH 101   108.0       229.23                                        
Lactose BP      156.18      --                                            
Magnesium Sterile BP                                                      
                0.875       0.875                                         
                350.0 mg    400.0 mg                                      
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 The figures in parentheses represent the weight of indoramin free base pe
 tablet.                                                                  
 
    
     The process used is described briefly below: 
     1. Screen indoramin embonate, Avicel, Lactose 40 mesh--mix in suitable mixer. 
     2. Wet granulate with water to produce dense mass. 
     3. Wet screen 12-14 mesh. 
     4. Dry granulate-screen 16-20 mesh. 
     5. Compress. 
     Cores made according to the above are then sprayed with a solution of one of the following enteric coatings: 
     
         ______________________________________                                    
Coating Composition                                                       
______________________________________                                    
(a)   Hydroxypropylmethyl cellulose phthalate                             
                                85%                                       
      Acetylated monoglyceride (Myvacet)                                  
                                10%                                       
      Talc                       5%                                       
(b)   Eudragit L30D             90%                                       
      Triacetin                 3.3%                                      
      Talc                      6.7%                                      
(c)   Polyvinyl acetate phthalate                                         
                                95%                                       
      Stearic acid               5%                                       
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     Water is a suitable solvent for coatings (a) and (b). For coating (c) a suitable solvent is a mixture of industrial methylated spirit/111 -trichloroethane. The enteric coating forms 3-5% of the tablet weight.