Development of a mold for capsule-shaped oral pulsatile delivery devices

INTRODUCTION In a recent work, the feasibility of injection-molding (IM) in the preparation of a shell device (ChronocapTM) for oral pulsatile delivery and/or time-dependent colonic release was demonstrated [1]. Capsular devices based on hydroxypropyl cellulose (HPC) showed the ability to delay, both in vitro and in vivo, the release of tracer drug powder as a function of the wall thickness and polymeric composition of the shell [1,2]. The mold prototype used offered several advantages, such as the preparation of matching caps and bodies within a single manufacturing cycle as well as of devices with differing nominal shell thicknesses of the thinner wall areas, e.g. the regions where body and cap were not overlapped because of the locking system. However, some limitations were highlighted with respect to the resulting device, such as the variability in the shell thickness and its poor consistency with the nominal value. Moreover, the rate of production and automation extent of the manufacturing process could be improved. The aim of the present work was therefore the design of a special mold, dedicated to the production of HPC-based capsules, and the subsequent development of a manufacturing process able to enhance the industrial scalability of this pulsatile delivery device. EXPERIMENTAL METHODS Materials -Hydroxypropyl cellulose (HPC, Klucel®LF, Aqualon, US; Eigenmann&Veronelli, I); polyethylene glycol (PEG1500, Clariant Masterbatches, I); acetaminophen (AAP, C.F.M., I). Rheological characterization -A rotational rheometer (ARES-2K, TA instruments, US) was used both in the temperature range of 180-280°C (gap=1mm; frequency=10rad/s; strain=0,1%; measures after 6min) and in isotherm (time from 0 to 1400sec; frequency=10rad/s; strain=0,2%; measures after 3min). Injection-molding process -A mixture of HPC 90% and PEG1500 10% was prepared in Turbula (Type T2C, WAB, CH), dried in a ventilated oven for 24 h at 40°C and then transferred into the injection-molding press (Baby Plast mod. 6/10P, Cronoplast E; Rambaldi S.r.l., I). IM process conditions are reported within the Results. In vitro release test – Each capsule body was manually filled with 80mg of acetaminophen powder, closed with a matching cap an sealed by applying a 3% w/v Klucel®LF aqueous solution to the junction area. A six-position USP34 disintegration apparatus was used; each unit was inserted in a basket-rack assembly (only one tube occupied) moving at 31 cycles/min in separate vessels with 900mL of deionized water (37±5°C) [3]. Fluid samples were assayed spectrophotometrically at 248nm. Lag time, i.e. the time to 10% release, and pulse time, i.e. the time elapsed between 90 and 10% release, were calculated from the release curves (n=6). RESULTS AND DISCUSSION An IM capsular shell with thickness of few hundreds µm and length as well as height around 10mm would fall within the definition of micromolded products [4]. Microinjection molding (µIM) is not only a simple scale-down of classical IM but also involves radical changes in machines, mold construction and raw materials. In particular, mold design, formulation development and setup of process parameters (e.g. mold temperature, injection speed and pressure, holding time and pressure) should be carried out concomitantly. However, formulation changes (e.g. percentage of plasticizer) at the current stage of development of the pulsatile delivery capsular device might impair the physical stability, release performance or mechanical characteristics. Therefore, in order to develop a robust manufacturing process, we focused on an in-depth evaluation of thermal, rheological and mechanical characteristics of the HPC-based formulation previously established (90% Klucel®LF and 10% PEG 1500, i.e. reference formulation) [1]. In the range of operating temperatures, the polymer viscosity tended to increase, which could be attributed to a possible rearrangement of the polymeric chains promoted by water loss (Fig. 1). Figure 1: absolute viscosity of Klucel®LF (green) and reference formulation (blue). Viscosity started decreasing only beyond 200ºC, that is at temperatures that cannot be exploited because of the polymer degradation. The viscosity of the polymeric reference formulation showed an analogous trend though it was always lower with respect to the polymer alone and seemed to be less affected by the hypothesized macromolecular chain rearrangement. Moreover, the formulation viscosity under isothermal conditions (T=190°C) demonstrated a tendency to increase over time (Fig. 2). These results confirmed the need for dealing with a plasticized formulation and indicated that not only operating temperatures, especially over 170-180°C, can be a critical issue, but also the time over which the material is maintained at this temperature, that can be correlated with the process cycle time. Figure 2: rheological parameters of the reference formulation: absolute viscosity (red), G’ storage modulus (blue), G’’ loss modulus (green), G’’/G’ (black). In order to avoid the polymer overheating, some changes were introduced into the press machine (piston and nozzle diameters were reduced), and the use of a hot runner was envisaged to allow the molten material to be heated until the cavity image port is reached. Finally, a new mold was designed, of constant 600µm nominal thickness, comprising the hot runner and two interchangeable inserts for the production of cap or body items. The improved characteristics of the mold are: i) central position of the injection orifice to allow a consistent flow length in all directions; ii) halved thickness in the overlapping end portions to ensure a constant thickness of the closed device; iii) length/diameter ratio reduced to 1.5; iv) inserted air ejection mechanism that prevents the need for lubricants. For the final rectification of the mold, mechanical tests were performed on the formulation, in order to verify its tendency to undergo dimensional changes after IM processes in different ranges of temperatures (shrinkage test, data not reported). Table I: IM process conditions Plasticating temperature; °C 100 Injecting temperature; °C 130 Nozzle temperature; °C 140 Hot runner temperature; °C 160 First injection pressure; bar 30 First injection time; s 0.5 Second injection pressure; bar 10 Second injection time; s 0.3 Cooling temperature; °C 15 Cooling time; s 2.5 Total cycle time; s 5 By the proper selection of operating parameters (Table I) it was possible to achieve a completely automated IM manufacturing process with a cycle time of about 5s for each item (cap or body), avoiding the use of internal or external lubrication. The technical drawing of the capsular device is reported in Figure 3. Figure 3: technical drawing of the capsular device. Because major changes were introduced into the system design, the capsule shells manufactured by the novel mold needed to be evaluated in terms of technological properties and release performance (Table II and Fig. 4). Table II: technological characteristics of the capsular devices (CV in brackets) weight; mg 228 (0.51) thickness; µm 610 (3.30) elastic modulus; N/mm2 3.509 (2.01) Figure 4: release profiles from capsular devices (average lag and pulse time in frame; standard deviation in brackets). The capsular devices prepared by the new mold demonstrated good technological properties and, as compared with the previous systems, improved reproducibility of shell thickness, mechanical properties, opening mechanism as well as release performance. AKNOWLEDGEMENTS The authors would like to thank Consorzio Proplast for technical support. REFERENCES [1] A. Gazzaniga et al., AAPS Pharm .Sci. Tech. 12(1), 295-303, 2011 [2] A. Gazzaniga et al., 38th CRS annual meeting and exposition, august 2011 [3] A. Gazzaniga et al., STP Pharm. Sci. 5, 83-88, 1995 [4] J. Giboz et al., J. Micromech. Microeng. 17, R96-R109, 2007