Directly compressible formulations of azithromycin

Abstract

The present invention relates to a dry blend, used for forming azithromycin tablets by direct compression, comprising non-dihydrate azithromycin and at least one pharmaceutically acceptable excipient. This invention also relates to an azithromycin tablet comprising non-dihydrate azithromycin and at least one pharmaceutically acceptable excipient. Preferably, the azithromycin tablet is formed by directly compressing the dry blend, of the present invention, to form said azithromycin tablet. Preferably, the azithromycin tablet, of the present invention, contains a dosage of 250 mgA, 500 mgA or 600 mgA of azithromycin. This invention further relates to an azithromycin tablet which is produced by forming a dry blend of a non-granulated azithromycin form A and at least one pharmaceutically acceptable excipient. The azithromycin tablet is then formed by directly compressing the dry blend.

We claim:  
     
         1 . A dry blend, used for forming azithromycin tablets by direct compression, comprising: 
 (a) non-dihydrate azithromycin; and    (b) at least one pharmaceutically acceptable excipient.    
     
     
         2 . A dry blend of  claim 1  wherein the non-dihydrate azithromycin is selected from the group consisting of forms B, D, E, F, G, H, J, M, N, O, P, Q, R, and mixtures thereof.  
     
     
         3 . A dry blend of  claim 2  wherein the non-dihydrate azithromycin is Form F azithromycin.  
     
     
         4 . A dry blend of  claim 2  wherein the non-dihydrate azithromycin is Form M azithromycin.  
     
     
         5 . A dry blend of  claim 1  wherein the non-dihydrate azithromycin is non-granulated.  
     
     
         6 . A dry blend of  claim 1  further comprising about 30-80%, by weight, of the non-dihydrate azithromycin.  
     
     
         7 . A dry blend of  claim 1  further comprising about 0.1-85%, by weight, of a diluent.  
     
     
         8 . A dry blend of  claim 7  further comprising 
 (a) from 30-80%, by weight, of the non-dihydrate azithromycin; and  
 (b) from 20-70%, by weight, of the diluent.  
 
     
     
         9 . A dry blend of  claim 8  wherein the diluent is selected from a group consisting of anhydrous lactose, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, dextrate, mannitol, sorbitol and dihydrated dibasic calcium phosphate.  
     
     
         10 . A dry blend of  claim 8  wherein the Carr's Compressibility Index, of the dry blend, is less than about 34%.  
     
     
         11 . A dry blend of  claim 8  wherein the Carr's Compressibility Index, of the dry blend, is less than about 31%.  
     
     
         12 . A dry blend of  claim 8  wherein the Carr's Compressibility Index, of the dry blend, is less than about 28%.  
     
     
         13 . A dry blend of  claim 1  further comprising from about 2-15%, by weight, of a disintegrant.  
     
     
         14 . A dry blend of  claim 13  further comprising: 
 (a) about 2-10%, by weight, of the disintegrant; and  
 (b) about 0.5-8%, by weight, of a lubricant.  
 
     
     
         15 . A dry blend of  claim 1  further comprising from about 0.25-10%, by weight, of a lubricant.  
     
     
         16 . A dry blend of  claim 15  further comprising from about 0.5-3%, by weight, of the lubricant.  
     
     
         17 . A dry blend of  claim 15  wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate and a mixture of magnesium stearate and sodium lauryl sulfate.  
     
     
         18 . A dry blend of  claim 1  further comprising a glidant.  
     
     
         19 . A dry blend of  claim 18  wherein the glidant is selected from the group consisting of magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, stearate salts and colloidal silicon dioxide.  
     
     
         20 . A dry blend of  claim 19  wherein the glidant is selected from the group consisting of talc, magnesium stearate and colloidal silicon dioxide.  
     
     
         21 . A dry blend of  claim 1  comprising: 
 (a) about 1-80%, by weight, non-dihydrate azithromycin;  
 (b) about 10-90%, by weight, binder;  
 (c) about 0-85%, by weight, diluent;  
 (d) about 2-15%, by weight, disintegrant; and  
 (e) 0.25-10%, by weight, lubricant.  
 
     
     
         22 . A dry blend of  claim 21  further comprising: 
 (a) about 2-10%, bt weight, disintegrant; and  
 (b) 0.5-8%, by weight, lubricant.  
 
     
     
         23 . A dry blend of  claim 21  wherein the non-dihydrate azithromycin is non-granulated.  
     
     
         24 . A dry blend of  claim 1  wherein the Carr's Compressibility Index, of the dry blend, is less than about 34%.  
     
     
         25 . A dry blend of  claim 1  wherein the Carr's Compressibility Index, of the dry blend, is less than about 31%.  
     
     
         26 . A dry blend of  claim 1  wherein the Carr's Compressibility Index, of the dry blend, is less than about 28%.  
     
     
         27 . A dry blend of  claim 1  wherein the internal angle of friction, of the dry blend, is less than about 34°.  
     
     
         28 . A dry blend of  claim 27  wherein the Carr's Compressibility Index, of the dry blend, is less than about 34%.  
     
     
         29 . A dry blend of  claim 1  wherein the internal angle of friction, of the dry blend, is less than about 31°.  
     
     
         30 . A dry blend of  claim 29  wherein the Carr's Compressibility Index, of the dry blend, is less than about 28%.  
     
     
         31 . A dry blend of  claim 1  wherein less than about 6% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 16 μm or less.  
     
     
         32 . A dry blend of  claim 2  wherein less than about 6% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 16 μm or less.  
     
     
         33 . A dry-blend of  claim 1  wherein less than about 20% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 44 μm or less.  
     
     
         34 . A dry blend of  claim 33  wherein less than about 14% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 44 μm or less.  
     
     
         35 . A dry blend of  claim 34  wherein less than about 60% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 105 μm or less.  
     
     
         36 . A dry blend of  claim 35  wherein less than about 50% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 105 μm or less.  
     
     
         37 . A dry blend of  claim 34  wherein less than about 27% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 74 μm or less.  
     
     
         38 . A dry blend of  claim 34  wherein less than about 6% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 16 μm or less.  
     
     
         39 . A dry blend of  claim 1  wherein, by volume as measured by the Malvern method, 
 (a) less than about 6% of the azithromycin particles have a diameter of about 16 μm or less; and  
 (b) less than about 20% of the azithromycin particles have a diameter of about 44 μm or less.  
 
     
     
         40 . A dry blend of  claim 39  wherein less than about 14% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 44 μm or less.  
     
     
         41 . A dry blend of  claim 1  wherein, by volume as measured by the Malvern method, 
 (a) less than about 6% of the azithromycin particles have a diameter of about 16 μm or less;  
 (b) less than about 20% of the azithromycin particles have a diameter of about 44 μm or less; and  
 (c) less than about 27% of the azithromycin particles have a diameter of about 74 μm or less.  
 
     
     
         42 . A dry blend of  claim 41  wherein less than about 14% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 44 μm or less.  
     
     
         43 . A dry blend of  claim 1  wherein, by volume as measured by the Malvern method, 
 (a) less than about 6% of the azithromycin particles have a diameter of about 16 μm or less;  
 (b) less than about 20% of the azithromycin particles have a diameter of about 44 μm or less;  
 (c) less than about 27% of the azithromycin particles have a diameter of about 74 μm or less; and  
 (d) less than about 60% of the azithromycin particles have a diameter of about 105 μm or less.  
 
     
     
         44 . A dry blend of  claim 43  wherein less than about 14% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 44 μm or less.  
     
     
         45 . A dry blend of  claim 43  wherein, by volume as measured by the Malvern method, 
 (a) less than about 14% of the azithromycin particles have a diameter of 44 μm or less; and  
 (b) less than about 50% of the azithromycin particles have a diameter of 105 μm or less.  
 
     
     
         46 . A dry blend of  claim 34  wherein the non-dihydrate azithromycin is non-granulated.  
     
     
         47 . An azithromycin tablet comprising non-dihydrate azithromycin and at least one pharmaceutically acceptable excipient.  
     
     
         48 . An azithromycin tablet of  claim 47  wherein said tablet is produced by: 
 (a) forming a dry blend of a non-dihydrate azithromycin and at least one pharmaceutically acceptable excipient; and  
 (b) direct compressing said dry blend to form the azithromycin tablet.  
 
     
     
         49 . An azithromycin tablet of  claim 48  wherein the non-dihydrate azithromycin, in the dry blend, is non-granulated.  
     
     
         50 . An azithromycin tablet of  claim 48  wherein the dosage of azithromycin in said tablet is selected from the group consisting of 250 mgA, 500 mgA and 600 mgA.  
     
     
         51 . An azithromycin tablet of  claim 50  wherein the non-dihydrate azithromycin, in the dry blend, is non-granulated.  
     
     
         52 . An azithromycin tablet of  claim 48  wherein the non-dihydrate azithromycin is selected from the group consisting of forms B, D, E, F, G, H, J, M, N, O, P, Q, R, and mixtures thereof.  
     
     
         53 . An azithromycin tablet wherein said tablet is produced by: 
 (a) forming a dry blend of a non-granulated azithromycin form A and at least one pharmaceutically acceptable excipient; and    (b) direct compressing said dry blend to form the azithromycin tablet.    
     
     
         54 . A pharmaceutical formulation comprises (a) about 80%, by weight, or more, of non-granulated azithromycin; and 
 (b) one or more pharmaceutically acceptable excipients.    
     
     
         55 . A pharmaceutical formulation of  claim 54  further comprising a capsule.  
     
     
         56 . A method of forming an azithromycin tablet, comprising: 
 (a) mixing particles of a non-dihydrate azithromycin and at least one pharmaceutically acceptable excipient to form a dry blend; and    (b) direct compressing said dry blend to form the azithromycin tablet.    
     
     
         57 . The method of  claim 56  wherein the non-dihydrate azithromycin is non-granulated.  
     
     
         58 . The method of  claim 57  further comprising the step of removing azithromycin fines from the non-dihydrate azithromycin.  
     
     
         59 . The method of  claim 57  further comprising the step of mixing a lubricant with the dry blend prior to direct compressing.  
     
     
         60 . The method of  claim 57  further comprising the step of precompressing the dry blend.  
     
     
         61 . The method of  claim 57  further comprising the step of force feeding the dry blend into a tableting means.  
     
     
         62 . The method of  claim 57  wherein the dry blend comprises: 
 (a) about 1-80%, by weight, non-dihydrate azithromycin;  
 (b) about 10-90%, by weight, binder;  
 (c) about 0-85%, by weight, diluent;  
 (d) about 2-15%, by weight, disintegrant; and  
 (e) 0.25-10%, by weight, lubricant.  
 
     
     
         63 . The method of  claim 57  wherein the dry blend has a Carr's Compressibility Index of less than about 34%.  
     
     
         64 . The method of  claim 57  wherein the dry blend has a Carr's Compressibility Index of less than about 31%.  
     
     
         65 . The method of  claim 57  wherein the dry blend has a Carr's Compressibility. Index of less than about 28%.  
     
     
         66 . The method of  claim 57  wherein the dry blend has an internal angle of friction of less than about 34°.  
     
     
         67 . The method of  claim 57  wherein the dry blend has an internal angle of friction of less than about 31°.  
     
     
         68 . The method of  claim 57  wherein less than about 6% of the total azithromycin particles, by volume as measured by the Malvern method, in the dry blend have a diameter of 16 μm or less.  
     
     
         69 . The method of  claim 57  wherein less than about 20% of the total azithromycin particles, by volume as measured by the Malvern method, in the dry blend have a diameter of 44 μm or less.  
     
     
         70 . The method of  claim 69  wherein less than about 14% of the total azithromycin particles, by volume as measured by the Malvern method, in the dry blend have a diameter of 44 μm or less.  
     
     
         71 . The method of  claim 69  wherein less than about 60% of the total azithromycin particles, by volume as measured by the Malvern method, in the dry blend have a diameter of 105 μm or less.  
     
     
         72 . The method of  claim 71  wherein less than about 50% of the total azithromycin particles, by volume as measured by the Malvern method, in the dry blend have a diameter of 105 μm or less.  
     
     
         73 . The method of  claim 69  wherein less than about 27% of the total azithromycin particles, by volume as measured by the Malvern method, in the dry blend have a diameter of 74 μm or less.  
     
     
         74 . The method of  claim 69  wherein less than about 6% of the total azithromycin particles, by volume as measured by the Malvern method, have a diameter of 16 μm or less.  
     
     
         75 . The method of  claim 57  wherein, by volume as measured by the Malvern method, in the dry blend 
 (a) less than about 6% of the azithromycin particles have a diameter of about 16 μm or less; and  
 (b) less than about 20% of the azithromycin particles have a diameter of about 44 μm or less.  
 
     
     
         76 . The method of  claim 75  wherein less than about 14% of the total azithromycin particles, by volume as measured by the Malvern method, in the dry blend have a diameter of 44 μm or less.  
     
     
         77 . The method of  claim 57  wherein, by volume as measured by the Malvern method, in the dry blend 
 (a) less than about 6% of the azithromycin particles have a diameter of about 16 μm or less;  
 (b) less than about 20% of the azithromycin particles have a diameter of about 44 μm or less; and  
 (c) less than about 27% of the azithromycin particles have a diameter of about 74 μm or less.  
 
     
     
         78 . The method of Claim,77 wherein less than about 14% of the total azithromycin particles, by volume as measured by the Malvern method, in the dry blend have a diameter of 44 μm or less.  
     
     
         79 . The method of  claim 57  wherein, by volume as measured by the Malvern method,in the dry blend 
 (a) less than about 6% of the azithromycin particles have a diameter of about 16 μm or less;  
 (b) less than about 20% of the azithromycin particles have a diameter of about 44 μm or less;  
 (c) less than about 27% of the azithromycin particles have a diameter of about 74 μm or less; and  
 (d) less than about 60% of the azithromycin particles have a diameter of about 105 μm or less.  
 
     
     
         80 . The method of  claim 79  wherein less than about 14% of the total azithromycin particles, by volume as measured by the Malvern method, in thr dry blend have a diameter of 44 μm or less.  
     
     
         81 . The method of  claim 57  wherein, by volume as measured by the Malvern method, in the dry blend 
 (a) less than about 14% of the azithromycin particles have a diameter of 44 μm or less; and  
 (b) less than about 50% of the azithromycin particles have a diameter of 105 μm or less.  
 
     
     
         82 . A method of treating a bacterial or protozoal infection in a mammal, comprising administering to said mammal an azithromycin tablet of claims  47 ,  48 ,  49 ,  50 ,  51 ,  52 , or  53 .  
     
     
         83 . A method of treating a bacterial or protozoal infection in a mammal, comprising administering to said mammal an azithromycin pharmaceutical formulation of  claim 54.