Could 3D printed waffle shapes replace the magistral preparation of hydrocortisone capsules for children’s personalized medicine?

INTRODUCTION
Adrenal insufficiency (AS) is a pathology that results in a disruption of the production of endogenous hormones, notably the adrenocorticotropic hormone (ACTH) and cortisone. Hydrocortisone (HCT) is mainly used in the substitution treatment of AS. The magistral preparation of HCT capsules in community pharmacies remains the only oral treatment adapted to paediatric population due to the low doses administered. However, these preparations show non-compliance in mass and content uniformity. Given the risk of overdose or underdose, a possible adrenal crisis as well as poor control of the disease cannot be excluded.
Three-dimensional (3D) printing appears as a potential solution. Indeed, the use of 3D printing for drug manufacturing has considerably increased in the pharmaceutical field in recent years. The possibility to print, on demand, solid oral forms with dosages adapted to the patient, thus to practise personalized medicine, is a reason why Fused Deposition Modeling (FDM) appears as a promising tool. Elaboration of new solid oral forms by hot-melt extrusion (HME) coupled to FDM can be a solution to improve the pharmaceutical quality of single-dose magistral preparations in comparison with the capsules currently produced in community pharmacies. Nevertheless, the FDM technique poses a challenge given the small size of the forms intended for children and the possibility of HCT degradation due to the high temperatures of the processes used. The goal of this work is therefore to develop low-dose solid oral forms containing HCT, of sufficient pharmaceutical quality, by HME and FDM for the treatment of the paediatric population against AS.

MATERIALS AND METHODS
Materials : The elaborated formulation contained 20% of HCT; 53.83% of Affinisol® 15LV (hydroxypropylmethylcellulose) and 23.07% of Kollidon® VA 64 (vinylpyrrolidone-vinyl acetate copolymer) as polymers; 3% of tri(ethyl)citrate as plasticizer and 0.1% of red iron oxide as dye.
Methods :
HME and FDM 3D Printing : HME (Pharma 11, ThermoFisher Scientific®, Waltham, MA, USA) was performed at 140°C and 50 rpm to produce three batches of filaments. 20 waffle shapes with diameters of 4.5, 6.0, 7.25 mm, heights of 2.0, 2.8 and 3.2 mm and drug loads of 2, 5 and 8 mg were respectively printed (Prusa® i3MK3 3D printer, Prague, Czech Republic). The settings were: extrusion temperature, 155 °C; infill density, 30%; nozzle diameter, 0.25 mm; outside shell thickness, 0 mm.
Since there is no monograph about printed forms, the monograph of uncoated tablets in European Pharmacopoeia 11th edition was used to characterize the printed forms.
High Performance Liquid Chromatography (HPLC) : The HCT content was evaluated on 10 printed forms by a validated HPLC method (Agilent® 1100, Santa Clara, USA). The limit set by the European Pharmacopoeia for content uniformity (monograph 2.9.40) is an acceptance value lower than 15.0, calculated with the following equations:
VA = ks (98.5 < X < 101.5%)
VA = 98.5 – X + ks (X < 98.5%)
VA = X – 101.5 + ks (X > 101.5%)
VA = Acceptance value; k = 2.4; s = standard deviation; X = Average of the individual contents expressed as a percentage of the content indicated on the label.
Dissolution Test : Dissolution studies were performed on six printed forms using the USPII paddle method in a Sotax® AT7 apparatus (Allschwil, Switzerland) in 500 mL of HCl 0.1 M during 2 h at 50 rpm and 37 °C. The limit set by the European Pharmacopoeia for conventional release solid forms (monograph 2.9.3) is a quantity of API released of at least 80% in 45 min or less. One-way ANOVA and Tuckey tests (p value of 0.01) were performed to statistically analyze inter-batch variabilities on GraphPad Prism® software (v. 5)
Friability : Friability test was performed on 20 printed forms using the friability tester (Fribilator USP F2, Sotax®). After rotating at 25 rpm for 4 min, the difference in total weight (%) before and after the test was calculated for the printed forms. The limit set by the European Pharmacopoeia (monograph 2.9.7) is a loose of total weight of 1% after the assay.
Stability study : The stability study was set-up according to the International Council for Harmonisation (ICH) guideline “Q1A(R2)” (2003). The printed forms were placed in climate chambers at the following condition of temperature and relative humidity (RH): 25°C ± 0.1°C/60% RH ± 0.5% RH. Tests were carried out every four weeks during 12 weeks.

RESULTS AND DISCUSSION
Formulation and Design Development
Drug Content : TEC acts as a plasticizer in the formulation to decrease the glass transition temperature (Tg) of polymers in order to print at lower temperatures. Indeed, HCT concentration decreased when the printing temperature exceeded 155°C, indicating drug degradation.
Drug Dissolution : In order to obtain a conventional release of the drug, like HCT capsules, printed forms with a low infill density (30%) have been developed because the more the infill density decreases, the more the dissolution rate of the active pharmaceutical ingredient (API) increases. In addition, the cylindrical design with an outline traditionally used did not give HCT the desired release. The outline of the shape has therefore been removed, to form a new 3D design similar to a waffle, increasing the release rate of HCT. Finally, a 0.25 mm diameter nozzle was used, unlike the 0.4 mm diameter nozzle traditionally used in FDM. Thus, the width of the layer of material deposited was finer and the dissolution rate of HCT was faster.
Final Formulation and Design
Content Uniformity : According to a study of Neumann et al. about the magistral preparation of HCT capsules in community pharmacies, out of 61 batches sent, 21.4% of them showed non-compliance. The content uniformity of 3D printed waffle shapes containing 2, 5 and 8 mg of HCT has shown encouraging results with a maximum acceptance value of 2.7, which was lower than the requested value of 15.0.
Printed Forms Friability : The difference in total weight (%) before and after the test was respectively of 0.40%, 0.55% and 0.77% for 3D printed waffle shapes containing 2, 5 and 8 mg of HCT. Thus, the printed forms comply with the specifications.
Drug Dissolution : 95.80 +/- 4.45%, 89.37 +/- 5.40%, 83.85 +/- 8.16% of HCT was released in 45 min for 3D printed waffle shapes containing 2, 5 and 8 mg of HCT respectively, indicating a conventional release. No significant difference in the amount of HCT released was shown between the different batches for printed forms containing the same HCT dosage.
Printed Forms Stability : Filaments and 3D printed waffle shapes containing 2, 5 and 8 mg of HCT demonstrated stability in terms of drug dissolution rate and content during 12 weeks of conservation under the applied conditions of storage.

CONCLUSION
Red 3D printed waffle shapes containing low-dose HCT for pediatric use were successfully developed by HME coupled to FDM. Content uniformity, drug dissolution and printed forms friability complied with the European Pharmacopoeia specifications, despite the considerable challenge of the their small dimensions. Furthermore, filament and printed forms demonstrated stability in terms of drug content and drug dissolution rate for 12 weeks. These results therefore indicate that 3D-printed solid oral forms would make it possible to offer patients a higher pharmaceutical quality than those of the magistral preparations of capsules containing low-dose corticosteroids currently used. Solid oral forms containing different dosages of API can be printed with the same filament, offering the prospect of practicing personalized medicine in community pharmacies. In the future, reproducibility studies could be carried out with a variation of the printer model and this technique could be transferred to other APIs.