Oral dosage forms with carvedilol fabricated by selective laser sintering (SLS) 3D printing technique

Abstract

1. INTRODUCTION When it comes to pharmacy, 3D printing has gained immense popularity in recent years due to its revolutionary use in printing drugs tailored to individual patient needs [1,2]. Selective laser sintering (SLS) is an industrial 3D printing technique which uses a powder bed to build up the 3D object thanks to a laser which binds the powder particles together. Advantages of SLS technique include the fact that it is a solvent-free process and offers relatively fast production. Until today, a limited number of studies investigating the production of drug dosage forms using SLS have been reported [2,3]. 2. MATERIALS AND METHODS 2.1. Materials Carvedilol (CRV) was used as a model substance in this study and it was donated by Hemofarm (Vršac, Serbia). The following excipients used to obtain 3D printing tablets: polyvinyl alcohol (PVA, Merck), mannitol (Parteck® M, Merck), Ludipress® (coprocessed excipient consisting of 93% lactose monohydrate, 3.5% crospovidone (Kollidon® CL) and 3.5% povidone K30 (Kollidon® 30), BASF), talc (Merck) and candurin (Candurin® Gold Sheen, Merck). 2.2. Preparation of formulations The compositions of the formulations are shown in Table 1. Table 1. Composition of the formulations Material Formulation 1 Formulation 2 CRV 10% 10% PVA 55% 55% Parteck® M 30% / Ludipress® / 30% Talc 2% 2% Candurin® Gold Sheen 3% 3% Powder for 3D printing was obtained by mixing all the components of the formulation and sifting through a sieve with a diameter of 180 μm. 2.3. 3D printing of oral dosage forms A cylindrical 3D models of the printed tablets (8.00 mm diameter and 2.00 mm thickness) were designed with Autodesk Fusion 360 software version 2.0.8809 (Autodesk Inc, San Rafael, CA, USA), exported as a stereolithography file (.stl) and printed with Sintratec Kit 3D printer (Sintratec AG, Switzerland). The printing parameters were controlled using Sintratec 3D printer software. After a series of variations in temperature and laser speed, the optimal values of these parameters used in the 3D printing process were established and shown in Table 2. Table 2. SLS 3D printing process parameters Surface Temperature ( ◦C) Chamber Temperature ( ◦C) Laser speed (mm/s) Hatch space 80 ºC 70 ºC 60 250 μm 2.4. Mechanical properties of 3D tablets Tablets (n = 10) were weighed on a Sartorius BP 210 D analytical balance (Sartorius, Goettingen, Germany) and measured (diameter and thickness) using a digital caliper (Vogel, Kevelaer, Germany). 2.5. Powder X-ray diffraction analysis (PXRD) PXRD analysis was performed to assess whether the laser induced amorphization of any of the compounds, especially amorphization of poorly soluble CRV. Samples were collected using a Philips PW-1050 (Philips, The Netherlands) diffractometer, operated at 40 kV and 30 mA, using Ni-filtered Cu Kα radiation. 2.6. Dissolution and Drug Release Analysis Dissolution testing was performed under nonsink conditions using mini paddle apparatus (Erweka DT 600, Germany) with a paddle rotation speed of 50 rpm for 8 h, in 100 ml of phosphate buffer (pH 6.8). The amount of dissolved CRV was determined by HPLC method using Dionex Ultimate 3000 (Thermo Scientific, USA) HPLC system. 3. RESULTS AND DISCUSSION 3.1. 3D printing process It was shown that SLS printer was able to fabricate 3D tablets with CRV, as well as that success of the printing process depended on the used printing parameters. 3.2. Mechanical properties of 3D tablets The dimensions of the obtained 3D tablets were in accordance with the defined values of the created 3D models (F1: 8.10 ± 0.08 mm diameter and 2.10 ± 0.13 mm thickness, F2: 8.13 ± 0.09 mm diameter and 2.10 ± 0.12 mm thickness). Significant variations in tablet weight between formulations were not observed (m1=0.146 ± 0.04; m2=0.136 ± 0.03). 3.3. Powder X-ray diffraction analysis (PXRD) Figure 1. The X-ray powder diffraction of F1 and F2. 3.4. Dissolution and Drug Release Analysis Figure 2. Dissolution profiles of 3D printing tablets 4. CONCLUSION SLA represents a new chapter in 3D printing of solid oral dosage forms and in individualized therapy in particular. By adjusting the formulation and process parameters, it was possible to produce SLS tablets with coamorphous CRV and PVA as a main polymer. Complete drug release was achieved under non sink conditions after 8 hours in phosphate buffer. The tailoring of drug release might be achieved by varying formulation factors as well as process parameters, although it could be governed by the composition of the whole formulation.