Abstract:
New formulations of spiramycin suitable for oral administration, particularly for children, comprise spiramycin and potassium acesulfame. These formulations mask the bitterness of spiramycin without adversely affecting the bioavailability or stability of the spiramycin. Preparation by wet granulation followed by dry state mixing is also disclosed.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This is a continuation-in-part (CIP) application of U.S. patent application Ser. No. 08/411,620 filed Apr. 5, 1995, now abandoned. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to new pharmaceutical formulations of spiramycin. It relates more particularly to new formulations intended to be administered orally. 
     BACKGROUND OF THE INVENTION 
     Spiramycin has been commercially available for nearly twenty-five years. However, spiramycin has proven very difficult to administer to man and, more particularly, to children in the form of a solution, suspension or dispersible granule because its bitterness is extremely difficult to mask. 
     Attempts to mask this bitterness include the formulation described in French published patent application number FR 2,669,533, which discloses spiramycin encapsulated by albumin by a technique which requires the use of organic solvents, such as isooctane, and their removal at the end of the process. This technique, although very efficient at taste-masking, is very expensive because it only allows the manufacture of small quantities of pharmaceutical composition and it necessitates stages of solvent recycling which are long and costly. 
     SUMMARY OF THE INVENTION 
     The present invention has made it possible to prepare spiramycin formulations having an enhanced taste without using solvent for its preparation. This enhanced taste masks the bitterness of spiramycin without adversely affecting bioavailability or stability of the spiramycin. The formulation comprises spiramycin and acesulfame, particularly potassium acesulfame. 
     The new pharmaceutical forms of spiramycin according to the present invention, which may also include flavoring agents, are intended to take the form of doses (sachets, bottles or packs with a measure, for example) containing a granulated powder to be dissolved or to be dispersed in water prior to administration to the patient. 
     This new granulated form, which can be suspended in water immediately before use, offers the following advantages: 
     ease of use during ambulatory treatment 
     accuracy of the unit dosage 
     easy suspension or dissolution in water 
     easy absorption. 
     Numerous various formulation trials attempting to mask the bitterness have been undertaken. None of them gave satisfactory results as regards the taste of the aqueous suspension obtained or as regards the bioavailability of the spiramycin after absorption. However, the association between potassium acesulfame and spiramycin according to the present invention surprisingly has made it possible to achieve this objective. 
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     New granulated pharmaceutical forms of spiramycin for oral administration according to the present invention are prepared by wet granulation of the spiramycin and sucrose, preferably in a weight ratio of about 1/1 to about 1/9, followed by preparing in a dry state a mixture of the granules previously obtained, acesulfame, flavorings and any remaining sucrose. 
     The new formulations according to the invention preferably comprise about 100,000 to about 5,000,000 IU spiramycin, about 10 to about 20 mg potassium acesulfame, about 20 to about 200 mg flavorings and about qs 1 to about 10 g sucrose. According to one preferred embodiment, such formulations comprise 375,000 IU spiramycin, about 10 to about 20 mg potassium acesulfame, 60 mg flavorings and about qs 3 g sucrose. These formulations are preferred. One of ordinary skill in the art will appreciate that the formulations of the present invention may be adapted according to the desired masking of the bitterness of the active ingredient by adding more or less potassium acesulfame. The flavorings may also be adapted to the taste and to the age of the child. 
     These formulations may be presented either in the form of doses as mentioned above or in the form of a solution or suspension prepared immediately before use. 
    
    
     The invention will be described more fully with the aid of the following examples, which should not be considered as limiting the invention. 
     COMPARATIVE EXAMPLE 1 
     
         ______________________________________spiramycin         86.190  mg (375,000 IU)Eudragit E 100 ®              70.00   mgmannitol qs        950.00  mgsodium saccharinate              25.00   mgstrawberry flavoring              40.00   mganhydrous colloidal silica              12.50   mgcellulose (microcrystalline)              25.00   mgpolyvidone         100.00  mgsucrose            97.50   mg              1250.00 mg______________________________________ 
    
     Trials with this type of formula were stopped, in spite of the success of the taste masking, because of poor bioavailability. 
     COMPARATIVE EXAMPLE 2 
     Development of a simple and rational formula by preparation of a granule (concentrated) composed of sugar and spiramycin; and flavoring of the primary granule by the addition, in an external phase, of sweeteners and flavorings simply by mixing. 
     The manufacture of the primary granule is performed in a Turbosphere mixer-granulator-drier and the preparation of the final mixture in a gravity mixer. 
     Theoretical unit formula: 
     
         ______________________________________spiramycin base   81.156  mg (375,000 IU)sucrose qs        1000.00 mg sucrose (Alveo sugar)              1960.00                      mg        externalbanana flavoring  40.00   mg        phase             3000.00 mg______________________________________ 
    
     A bioavailability study demonstrated the bioequivalence of the granule of comparative trial 2 and of commercial syrup; however, the taste acceptability tests showed that the flavoring of the product requires improvements. 
     COMPARATIVE EXAMPLES 3 AND 4 
     The sweeteners commonly used (sodium saccharinate, sodium cyclamate) could not be selected because of the insufficient organoleptic effects. 
     An acceptability test was carried out on two of these formulations (one with sodium saccharinate (Example 4) and one with aspartame (Example 3)). The general formulations and results are indicated in Table 1 below. For aspartame, the taste acceptability test is satisfactory but the product interacts with spiramycin, thereby making its use impossible. 
     COMPARATIVE EXAMPLE 5 
     An attempt to mask the bitterness of spiramycin by association with xanthan gum. The general formulation is shown in Table 1. Results of taste testing were inconclusive but low. 
     EXAMPLE 6 
     The manufacture of sachets is carried out in 3 phases: 
     (a) Preparation of a concentrated primary granule (165 mg per sachet of 3 g containing 375,000 IU of spiramycin) in a Moritz mixer-granulator-drier: 
     
         ______________________________________per sachet of 3 g______________________________________spiramycin base   84.081   mg (375,000 IU)sucrose (superfine sugar)             qs 165.00                      mgwater             about 5% by mass______________________________________ 
    
     During the granulation, the product is heated with the aid of a jacket up to about 55° C. The stirring is carried out at about 100 revolutions/minute for 30 minutes. For the drying, the stirring is carried out at about 20 revolutions/minute while the temperature is maintained but while the pressure is reduced to between 6 and 20 KPa for 60 minutes. 
     The product is then cooled to room temperature over about 30 minutes. 
     The granule is sieved on a screen with a mesh of 0.71 mm. 
     (b) Preparation of the final granule in a cubic gravity mixer 
     
         ______________________________________primary granule        165.00  mgpotassium acesulfame   10.00   mgpowdered strawberry flavoring                  30.00   mgpowdered raspberry flavoring                  30.00   mgsucrose* qs            3000.00 mg______________________________________ *superfine sugar and Alveosugar in a 1/1 ratio approximately. 
    
     (c) Distribution of the final mixture in an amount of: 
     3 g for the 375,000 IU dosage 
     6 g for the 750,000 IU dosage 
     12 g for the 1,500,000 IU dosage 
     per sachet of paper/aluminum/polyethylene complex. 
     EXAMPLE 7 
     The procedures of Example 6 are repeated using qs 1 g sucrose in phase (a) per sachet of 3 g and 20 mg potassium acesulfame in phase (b). 
     The preparations described above (Examples 2-7) were submitted to taste testing and rated on a scale of 1 to 20 where 20 was the highest score. The results are set forth in Table 1. 
     
                       TABLE 1______________________________________COMPARATIVE EXAMPLES 2 TO 5                    INVENTIONC.sub.5    C.sub.2 C.sub.4 C.sub.3 7     6______________________________________spira- 375,000 375,000 375,000                        375,000 375,000                                      375,000mycin(IU)sucrose        qs 1 g        qs 1 g  qs 1 g                                      qs                                      165 mgstarch 3.5 mgxanthan   15 mggumPVP                    100 mgK ace-                               20 mg 10 mgsulfameaspartame                    10 mgsacchari-               25 mgnateEudragit                70 mgE ®mannitol               800 mgflavorings   20 mg  40 mg    40 mg                        20 mg   60 mg 60 mgsucrose  qs 2.5 g          qs 3 g  qs 1.25                        qs 3 g  qs 3 g                                      qs 3 gscore out  6.25    poor          14      15    accept-of 20                  non-bio                        inter-        ableremarks                equiva-                        action                  lent  between                        spiramycin                        and                        aspartame______________________________________ 
    
     The formulations according to the present invention (Examples 6 and 7) show a marked improvement compared with the prior art formulations regarding masking of the taste and aftertaste of spiramycin. 
     The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than the specification, as indicating the scope of the invention.