Abstract:
An aqueous suspension containing methyldopa and sucrose is disclosed. This composition is an oral dosage form for treating hypertension that is bioavailable.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of U.S. application Ser. No. 965,462 filed Dec. 1, 1978, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention concerns a liquid suspension containing methyldopa useful for oral treatment of hypertension. 
     Methyldopa (L-3-(3,4-dihydroxyphenyl)-2-methylalanine) is a known antihypertensive agent. It is generally administered orally for treating a hypertensive patient. The dosage form commonly used is a tablet. In some instances e.g. with children or the very elderly, administration of methyldopa in a palatable, liquid dosage form would be advantageous provided that it had a bioavailability at least equivalent to that of the tablet form. 
     Such a liquid pharmaceutical composition containing methyldopa has been discovered. 
     SUMMARY OF THE INVENTION 
     A liquid pharmaceutical composition for treating hypertension containing methyldopa and sucrose. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     An embodiment of the present invention is a pharmaceutical composition for treating hypertension in humans comprising an aqueous suspension containing methyldopa and sucrose. 
     This suspension can contain from about 15 mg to about 100 mg of methyldopa per milliter (ml) of aqueous suspension. It will preferably contain from 25 mg. to 100 mg. of methyldopa, and most preferably about 50 mg. of methyldopa, per ml. of said suspension. 
     The suspension must also contain from about 1 mg. to about 24 mg. of sucrose per mg. of methyldopa. Preferably, the suspension will contain from about 1 mg. to about 12 mg. of sucrose per mg. of methyldopa; more preferably the weight ratio of methyldopa:sucrose is about 1:2 to about 1:10 and most preferably about 1:10. 
     In addition to the essential ingredients, methyldopa and sucrose, the composition of the present invention can contain other ingredients conventionally used to prepare a pharmaceutically useful suspension. Such ingredients include antioxidants, e.g. sodium bisulfite, disodium edetate and citric acid, thickening/suspending agents, e.g. xanthan gum and Veegum K, flavorings, preservatives, coloring agents and the like. Conventional procedures and equipment are used to prepare the present suspensions. 
     An outstanding characteristic of the present suspension is that the bioavailability of the methyldopa is equal to or greater than methyldopa administered in conventional tablet form. When sorbitol, which is very commonly used to prepare pharmaceutically useful suspensions, is substituted for the sucrose in the present suspension, the bioavailability of the methyldopa is substantially less than methyldopa administered as a tablet. This is indeed surprising since sorbitol is reported to enhance the bioavailability of other pharmaceutically active compounds such as vitamins, (C &amp; E, News, p. 59-60, February 24, 1958). 
     The bioavailability of methyldopa was determined in vivo by measuring the concentration of methyldopa and conjugated methyldopa in the plasma and urine of humans subjects to whom 500 mg of methyldopa were administed in standard tablet form and in suspension form. The suspension and standard tablet formulations (A, B &amp; C) and bioavailability data are presented in the following tables: 
     
                       TABLE I______________________________________ METHYLDOPA FORMULATIONS A, B, &amp; C______________________________________             A         B             Sorbitol  Sucrose             Suspension                       SuspensionIngredients       mg/ml     mg/ml______________________________________Methyldopa Anhydrous             50        50Keltrol           3         --Avicel RC-591     --        10Ethyl Alcohol     0.0116 ml 0.0116 mlDisodium Edetate  0.5       0.5Sodium Bisulfite  2         2Citric Acid       1         1Polysorbate 80    0.2       0.2Orange Flavor     0.004 ml  0.004 mlPineapple Flavor  0.002 ml  0.002 mlPreservatives     1-1.4     1-1.4Sorbital Solution 70%             0.73 ml   --Sucrose           --        500Purified water  qsad             1 ml      1 ml______________________________________                CIngredients          Standard Tablet______________________________________Methyldopa              250    mg.Acid Citric Anhyd.      4.3    mg.No. 80 Powder USPCalcium Disodium Edetate USP                   0.2    mg.Ethyl Cellulose NF N 100                   20.0   mg.Ethyl Cellulose NF N 100                   6.16   mg.(as 8% solution in 20620Alcohol AS3A anhydrous)Alcohol SD3A Anhydrous  --Guar Gum Jaguar A-20-B  15.0   mg.Solka Floc Dev 2030     12.0   mg.Cab-O-Sil M-5           2.0    mg.Magnesium Stearate USP  1.43   mg.______________________________________Pre-Coating          Per Tablet______________________________________Hydroxypropyl Methylcellulose                1.25 mg.NF 50 cpsDiethyl Phthalate    0.30 mg.______________________________________ 
    
     
                       TABLE II______________________________________Bioavailability Data______________________________________                .sup.a Mean urinary recovery. Total               0-36 hours - α methyldopa plusA.  Urinary         conjugate in mg______________________________________    Standard Tablet C               151    Sorbitol Composition A               73.4    Sucrose Composition B               192______________________________________               .sup.b Mean plasma concentrations               at 4 hours - α methyldopa plusB.  Plasma Concentrations               conjugate in mcg/ml______________________________________    Standard Tablet C               4.02    Sorbitol Composition A               2.09    Sucrose Composition B               4.51______________________________________  .sup.a Data from nine human subjects after administration of a 500 mg dose of methyldopa in either tablet or suspension form in crossover studies.  .sup.b Data from nine human subjects after administration of a 500 mg dose of methyldopa in either tablet or suspension form in crossover studies. 
    
     These measurements (in Table II) show the bioavailability of methyldopa in the suspension containing sucrose form is superior to the tablet or suspension containing sorbitol forms. 
     Following are formulations illustrating the compositions of the present invention: 
     
         __________________________________________________________________________           SUSPENSIONS FORMULATIONSIngredient        I       II      III     IV__________________________________________________________________________Methyldopa USP Milled (Anhydrous)             50.0 mg.                     50.0 mg.                             100  mg.                                     100  mg.Microcrystalline Cellulose andSodium CarboxymethylcelluloseNF (Avicel RC591 NF)             10.0 mg.                     10.0 mg.                             10.0 mg.                                     10.0 mg.Disodium Edetate USP             0.50 mg.                     0.50 mg.                             0.50 mg.                                     0.50 mg.Sodium Bisulfite USP             2.00 mg.                     2.00 mg.                             2.00 mg.                                     2.00 mg.Citric Acid Monohydrate             1.00 mg.                     1.00 mg.                             1.00 mg.                                     1.00 mg.Sugar USP Med. Gran.             500  mg.                     200  mg.                             500  mg.                                     200  mg.Glycerin USP      10.0 mg.                     10.0 mg.                             10.0 mg.                                     10.0 mg.Ethyl Alcohol USP 95%             0.011                  ml.                     0.011                          ml.                             0.011                                  ml.                                     0.011                                          ml.Polysorbate 80 USP             0.20 mg.                     0.20 mg.                             0.20 mg.                                     0.20 mg.Benzoic Acid      1.00 mg.                     1.00 mg.                             1.00 mg.                                     1.00 mg.Orange Flavor Comp.Fritzsche Dodge &amp; Olcott 16242             0.0004                  ml.                     0.0004                          ml.                             0.0004                                  ml.                                     0.0004                                          ml.Pineapple Art. FlavorFritzsche Dodge &amp; Olcott 05194             0.0002                  ml.                     0.0002                          ml 0.0002                                  ml.                                     0.0002                                          ml.Water Purified USP  q.s.             1.0  ml.                     1.0  ml.                             1.0  ml.                                     1.0  ml.__________________________________________________________________________