Pharmaceutical formulation and process comprising a solid dispersion of macrolide (tacrolimus)

A process for preparing a pharmaceutical formulation comprising a pharmaceutically acceptable amount of a macrolide compound of the formula (I):

• wherein each vicinal pair of R1 and R2, R3 and R4, R5 and R6 independently may,
• a) represent two vicinal hydrogen atoms, or
• b) form a second bond between the vicinal carbon atoms to which they are attached;
• in addition to the meanings above, R2 may represent an alkyl group;
• R7 represents hydrogen, hydroxy group, protected hydroxy or alkyloxy group or, in conjunction with R1, it may represent oxo group;
• R8 and R9 independently represent hydrogen or hydroxy group;
• R10 represents hydrogen, alkyl group, alkyl group substituted by one or more hydroxy groups, alkenyl group, alkenyl group substituted by one or more hydroxy groups, or alkyl group substituted by oxo group;
• X represents oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or —CH2O—;
• Y represents oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or N—NR11R12 or N—OR13;
• R11 and R12 independently represent hydrogen atom, or alkyl, aryl or tosyl group;
• R13, R14, R15, R16, R17, R18, R19, R22 and R23 independently represent hydrogen atom or alkyl group;
• R20 and R21 independently represent oxo group, or they may independently represent (R20a, hydrogen atom) and (R21a, hydrogen atom) respectively;
• R20a and R21a independently represent hydroxy group, alkyloxy group, or OCH2OCH2CH2OCH3 or R21a is protected hydroxy group;
• in addition R20a and R21a may together represent an oxygen atom in an epoxide ring;
• n is 1, 2 or 3;
• in addition to the meanings above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6-membered N-, S- and/or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl group, hydroxy group, alkyl group substituted by one or more hydroxy groups, alkyloxy group, benzyl and —CH2Se(C6H5);
• in an oral dosage form, wherein the oral dosage form comprises a solid dispersion of a macrolide compound of formula (I) and a non-dispersed, non-dissolved, crystalline form of the macrolide compound, wherein the amount of the solid dispersion of the macrolide compound is from about 50% to about 85% of the combined amount of the solid dispersion and the non-dispersed, non-dissolved crystalline form, wherein the combined amount equals 100% of a pharmaceutically acceptable amount;
• wherein said solid dispersion of the macrolide compound is prepared by:
• a) dissolving from about 50% to about 85% of the total amount of the macrolide compound to be used in the formulation in a solvent to form a macrolide solution;
• b) mixing the macrolide solution of step (a) with one or more carriers;
• c) drying the mixture on the carrier(s) to form said solid dispersion;
• further wherein said solid dispersion is then processed as follows:
• d) milling said solid dispersion of step c) with the remainder of the total amount of the macrolide compound, filler materials and/or disintegrants;
• e) blending the milled materials of step d);
• adding lubricants and blending to form a final blend;
• g) forming the final blend into an oral dosage form.