Non-nanoparticulate application forms of macrolides

Mucoadhesive layer according to any one of the foregoing claims, wherein the mucoadhesive layer comprises

• a mucoadhesive polymer, preferably a polymer selected from a) amphiphilic polymers and hydrophilic polymers, b) poly(methacrylates), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising polyvinyl acetate and/or polyvinylpyrrolidone, and combinations thereof;
• wherein, preferably,
• the amphiphilic polymers are selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, polyoxyl castor oils and D-α-tocopherol-polyethylenglycol-succinate (TPGS), and/or
• the poly(methacrylates) are selected from neutral protonizable poly(methacrylates) and cationic poly(methacrylates), preferably selected from copolymers of dialkylaminoethyl methacrylates and methacrylic acid ester(s), and copolymers of trialkylammonioethyl methacrylates and methacrylic acid ester(s), in particular copolymers of dimethylaminoethyl methacrylates and methacrylic acid esters, and copolymers of trimethylammonioethyl methacrylates and methacrylic acid esters;
• and wherein the mucoadhesive layer further comprises:
• a cellulose derivative, preferably selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and a combination thereof;
• a plasticizer;
• preferably selected from glycerol, polyethylene glycol, e.g. low molecular weight polyethylene glycol such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributylcitrate;
• more preferably glycerol;
• optionally a colorant, preferably TiO2;
• and the non-nanoparticulate macrolide.

Mucoadhesive layer according to any one of the foregoing claims, wherein the mucoadhesive layer comprises

• a) a mucoadhesive polymer, preferably an amphiphilic polymer;
• hydroxypropyl cellulose (HPC);
• carboxymethyl cellulose (CMC);
• a plasticizer, preferably glycerol;
• and optionally a colorant, preferably TiO2;
• preferably 10 wt %-30 wt % of mucoadhesive polymer;
• 25 wt %-35 wt % of hydroxypropyl cellulose (HPC);
• 10 wt %-25 wt % of carboxymethyl cellulose (CMC);
• 10 wt %-16 wt % of said plasticizer;
• and optionally 1 wt %-4 wt % of said colorant;
• or
• b) a mucoadhesive polymer, preferably selected from crosslinked polyacrylic acid polymers and copolymers of methyl vinyl ether and maleic anhydride;
• hydroxypropyl cellulose (HPC);
• ethyl cellulose (EC);
• a plasticizer, preferably glycerol;
• and optionally a colorant, preferably TiO2;
• preferably 2 wt %-17 wt % of mucoadhesive polymer;
• 30 wt %-70 wt % of hydroxypropyl cellulose (HPC);
• 5 wt %-40 wt % of said ethyl cellulose (EC);
• 3 wt %-20 wt % of said plasticizer;
• and optionally 1 wt %-5 wt % of said colorant.

A mucoadhesive film, preferably mucoadhesive buccal film, comprising a mucoadhesive layer, a backing layer, and an intermediate layer,

• wherein said intermediate layer is arranged between the mucoadhesive layer and the backing layer, and wherein said mucoadhesive layer comprises a macrolide, preferably tacrolimus;
• wherein, preferably, said intermediate layer facilitates adhesion between the mucoadhesive layer and the backing layer;
• wherein, optionally, said intermediate layer comprises a plasticizer, preferably selected from glycerol, polyethylene glycol, e.g. low molecular weight polyethylene glycol such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributylcitrate, more preferably glycerol;
• wherein, optionally, said intermediate layer comprises a polymer, preferably a polymer comprising polyvinyl acetate and/or polyvinylpyrrolidone, more preferably a vinylpyrrolidone-vinyl acetate copolymer.

A method of preparing a mucoadhesive film, comprising

• i) providing a micronized macrolide, preferably non-nanoparticulate micronized macrolide;
• and a polymer mixture, wherein said polymer mixture comprises
• a mucoadhesive polymer, preferably a polymer selected from a) amphiphilic polymers and hydrophilic polymers, b) poly(methacrylates), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising polyvinyl acetate and/or polyvinylpyrrolidone, and combinations thereof;
• a cellulose derivative, preferably selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and a combination thereof;
• optionally, a plasticizer;
• preferably selected from glycerol, polyethylene glycol, e.g. low molecular weight polyethylene glycol such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributylcitrate;
• more preferably glycerol;
• optionally a colorant, preferably TiO2;
• ii) optionally, dispersing the micronized macrolide in a liquid medium to obtain a micronized macrolide dispersion and/or dissolving said micronized macrolide in an organic solvent to obtain a micronized macrolide solution;
• iii) mixing the micronized macrolide, optionally micronized macrolide dispersion or micronized macrolide solution, with the polymer mixture to obtain a mucoadhesive layer composition;
• iv) preparing a mucoadhesive layer using the mucoadhesive layer composition;
• optionally by coating the mucoadhesive layer composition on a surface, preferably on a process liner, e.g. by coating, hot melt extrusion, and/or casting;
• v) optionally, drying said mucoadhesive layer, thereby obtaining the mucoadhesive film comprising said mucoadhesive layer.