(M1030-08-50) Enhancing Capsule Swallowability via Double-Layer Design for Superior Glide in Wet Conditions

Purpose: Swallowability of oral dosage forms is key to their acceptance by patients, especially in specific subgroups such as pediatric and geriatric populations. Thus, to enable a smooth transit in the esophagus, capsules are recommended to be taken with a minimum volume of 100 ml (corresponding to a small glass of water). These recommendations are not always followed [1,2] and low co-administration volumes can result in esophageal retention of these dosage forms [3], induced by the natural mucoadhesive properties of gelatin and hypromellose (HPMC), the two main polymers used in capsule manufacturing [4]. The objective of this study is to develop a customized HPMC-based capsule with (i) enhanced glide properties to facilitate capsule swallowing and (ii) similar disintegration as >standard Vcaps® Plus (VCP) HPMC capsules.

Methods: Capsule manufacturing: Size #00 capsules were manufactured on pilot-scale capsule manufacturing equipment (Mini-Dipper) using Lonza’s double dipping proprietary technology [5]. These prototype capsules presented an inner HPMC layer (same composition as in VCP), and a functional outer layer based on Opadry® EZ (Colorcon). Capsule dimensions of prototype capsule bodies and caps were measured and compared to standard VCP capsule dimensions as reported in the Technical Reference File. Time to first opening of prototype and standard VCP capsules was defined as the time required to detect the encapsulated dye (Purple carrot powder 0.1%w/w in lactose) in the buffer (pH 6.8, buccal pH). These measurements were conducted on 6 capsules, using a disintegration apparatus (DT2 apparatus, Sotax), at 37°C. Capsule material glide properties were evaluated on polymer films. Two films were prepared to present the same thickness and composition as capsule shells: a bilayer film made of a HPMC and Opadry® EZ layers, and a film composed a HPMC only. Glide properties of the films were evaluated by two different methods: (1)Tribology measurements were performed on wetted films, using a rheometer (MCR302, Anton Paar) equipped with a tribo-rheology cell. Results were presented as Stribeck curves. (2)Friction measurements were conducted with a texture analyzer (TA.XT.Plus, Stable Micro Systems) which measured the force required to drag a piece of film with standardized dimensions fixed under a 73 g sled and pulled across a wetted aluminum surface at 8 mm/s. Force measurements were further used to calculate the associated static and dynamic friction coefficients.

Results: Bilayer HPMC/Opadry® EZ capsules were successfully obtained with uniform appearance and slightly rough feel, Figure 1 (a). These capsules presented similar dimensions as standard VCP capsules, Table 1, which is a promising indication of capsule machinability on standard capsule filling machines. Prototype and VCP capsules time to first opening were respectively measured at 04:09 ± 00:51 minutes and 04:27 ± 1:26 minutes in pH 6.8, Figure 1 (b). These results indicate that the disintegration properties of the capsules were not affected by the integration of an Opadry® EZ layer in the outer part of the capsule shell and that capsules will not prematurely open in patients’ mouth or esophagus. Glide properties of the capsule shell materials was evaluated on films with 2 different methods. Stribeck curves show how external film surface interacts with a given surface: VCP film curves (in red shades) show more frictional interaction than HPMC/Opadry® EZ curves (in blue shades) with the same smooth surface, Figure 2 (a). These observations were confirmed by the friction curves showing that both static friction (stiction) and dynamic friction are lower for HPMC/Opadry® EZ films (1.03 ± 0.21 g and 0.32±0.05 g ) than for standard VCP films (2.65 ± 1.12 g and 0.99 ± 0.30 g), Figure 2 (b) and (c).

Conclusion: Size #00 HPMC/Opadry® EZ customized double layer capsules improve capsule glide properties with potential for improved swallowability.

References: [1] J. Fuchs, The amount of liquid patients use to take tablets or capsules, Pharm Pract (Granada) 7 (2009) 170–174. https://doi.org/10.4321/s1886-36552009000300007.
[2] B. Hens, J.V.D. Abeele, J. Rubbens, M. Keirsebilck, J. Roelens, C. Schreurs, K. Verheyen, M. Casteels, G. Laekeman, P. Augustijns, Evaluation of real-life dosing of oral medicines with respect to fluid and food intake in a Dutch-speaking population, Journal of Clinical Pharmacy and Therapeutics 42 (2017) 467–474. https://doi.org/10.1111/jcpt.12535.
[3] L. Heidrich, F. Mankertz, M. Grimm, Swallowability and esophageal transit of different hard capsule shells, in: Porto, Portugal, 2025.
[4] R.-A. Vlad, A. Pintea, C. Pintea, E.-M. Rédai, P. Antonoaea, M. Bîrsan, A. Ciurba, Hydroxypropyl Methylcellulose—A Key Excipient in Pharmaceutical Drug Delivery Systems, Pharmaceutics 17 (2025) 784. https://doi.org/10.3390/pharmaceutics17060784.
[5] X. He, L. Palangetic, S. Vanquickenborne, J. Cuevas, Double layered delayed-release hard capsules, US20230414524A1, 2023. https://patents.google.com/patent/US20230414524A1/en (accessed March 17, 2025).

Figure 1: (a) Size #00 double layer HPMC/Opadry®EZ white capsules obtained on Mini-Dipper, (b) Time to first opening of standard VCP and prototype capsules opening in pH 6.8 buffer (n=6)

Figure 2: Film gliding property comparison between standard VCP and HPMC/Opadry®EZ prototype films: (a) Stribeck Tribology curves obtained with wet films (b) Representative friction measurement curves obtained with Texture analyzer, (c) Static and dynamic friction factors, n=10

Table 1: Dimensions of Vcaps® Plus capsules as reported in Technical Reference File and dimensions of prototype HPMC/Opadry®EZ capsules (n=20)