Pharmaceutical Development of Film-Coated Mini-Tablets with Losartan Potassium for Epidermolysis Bullosa

Abstract

Epidermolysis bullosa is a genetically heterogenous skin fragility disorder with multiorgan involvement appearing already in newborn children. Severe progressive fibrosis follows skin blistering, mucosa lesions, and wound healing, favouring development of highly aggressive squamous cell carcinomas. Losartan potassium (LP) has been described to show positive effects; therefore, it was of clinical interest to develop 2 mm mini-tablets with LP for treatment of the affected children. Several challenges emerged during development: limited flowability and sticking to punches were observed in the first tableting experiments due to a high drug load, and a bitter taste of the LP was reported. Sticking to punches was reduced by using SMCC 50 and a combination of different lubricants; however, direct compression trials on a Korsch XM 12 rotary press were not successful due to compaction phenomena in the hopper. Thus, an intermediate dry granulation was successfully introduced. Two final formulations of the mini-tablets complied with the requirements of the European Pharmacopoeia regarding disintegration times (<15 min) and friability (<1.0%); mean tensile strengths amounted to about 1 MPa as a compromise between manufacturability and sufficient mechanical strength for further coating studies. The subsequent coating step succeeded delaying the initial drug release for more than 2 min. An acceptance value ≤15 was matched for the coated mini-tablets, and stability studies showed a promising shelf life.

Keywords: coating; dry granulation; epidermolysis bullosa; losartan potassium; mini-tablet; paediatrics; rare disease; stability.

Figure 1

SEM image of losartan potassium with 730-fold magnification.

Figure 2

(a) Sticking on punches (upper punch displayed), leading to (b) damaged mini-tablets of F 6 with SMCC 50 and 3% SSF.

Figure 3

Comparison of (a) tabletability (mean ± CI (α = 0.05), n = 10) and (b) disintegration times (n = 6) of mini-tablets of F 8 produced on the STYL’One and on the Korsch XM 12; (a) also shows the tabletability (mean ± CI (α = 0.05), n = 10) of F 9 produced on the Korsch XM 12.

Figure 4

(a) Cumulative and (b) density particle size distribution (PSD) of granules (F 10) obtained at different specific compaction forces (2, 4, and 6 kN/cm); mean ± SD, n = 3.

Figure 5

Comparison of (a) tabletability (mean ± CI (α = 0.05), n = 10) and (b) disintegration times (n = 6) of mini-tablets of F 10A, 10B, 10C, and 11.

Figure 6

The µCT images of coated mini-tablets of (a) F 10C and (b) F 11.

Figure 7

Dissolution profiles of coated and uncoated mini-tablets of F 10C (A) and 11 (C) and the respective magnification of the profiles in the first minutes (B,D); 37 ± 0.5 °C, medium: phosphate buffer pH 6.0; n = 3.

Figure 8

(a) Content (mean ± CI (α = 0.05), n = 10) and (b) drug release in % at 30 min (n = 3) of coated mini-tablets (F 10C and F11) stored at 40 °C/75% r.h. and 25 °C/60% r.h. in different packaging conditions (openly, in polyethylene bags (PE), and in sealed aluminium foil (Alu)). Selected timepoints: 0 months (0 m), 3 months (3 m), and 6 months (6 m) of storage.