Facilitating encapsulation of permeation enhancers in customized low water permeability enteric capsules

This poster has been presented at the 15th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, which took place in Prague, Czech Republic.

Facilitating encapsulation of permeation enhancers
in customized low water permeability enteric capsules

Introduction

Oral bioavailability of large molecules remains a major challenge in the pharmaceutical industry. Indeed, most emerging drug modalities, including peptides, PROTACs, and siRNA, exceed 500 Da in molecular weight, which seriously limits their absorption along the gastro-intestinal tract. Consequently, these molecules are typically delivered via subcutaneous injection to ensure systemic exposure, despite the drawbacks of invasiveness and reduced patient adherence

To overcome these limitations, formulation strategies aimed at enhancing oral absorption are gaining increasing attention. Among them, the use of permeation enhancers such as sodium caprate (C10) has shown promise in improving intestinal permeability [1,2]. In parallel, enteric dosage forms offer protection against gastric acidity and enzymatic degradation while enabling targeted release in the small intestine[3], where the surface area for absorption is maximal. Ready-to-fill bilayer enteric capsules represent a practical solution to achieve enteric protection without additional coating steps.

The objective of this study is to develop (1) a formulation suitable for large-scale capsule filling incorporating a high amount of C10, and (2) a capsule with preserved enteric properties with high level of C10 to support the oral delivery of new drug modalities.

Methods

Material
Optimized C10 was kindly provided by Ashland. Vivapur®102 (MCC) was provided by JRS and magnesium stearate (MgSt) was acquired from Sigma. Size #0 Capsugel® Enprotect® capsules were manufactured at industrial scale.

Formulation preparation

70% C10 was first blended with 29.5% MCC during 10 min at 49 rpm using a Turbula® mixer (Erweka). 0.5 MgSt was added to the pre-blend which was mixed at 100 rpm for 2 additional min.

C10 and formulations characterization

Optical Particle Size Distribution (OPSD) of C10 was evaluated with Morphologi 4 (Malvern).

Flowability and compressibility behavior of C10 and associated formulation were tested on Erweka GT and SVM II (Erweka). Slug test was performed on C10 and C10-based formulation to evaluate their ability to form a plug to be filled in size #0 capsules using a slug tester (Sauter). Plugability is used to evaluate the encapsulation ability of powders on tamping filling machines.

Capsule manufacturing and characterization

Customized size#0 HPMC/HPMC-AS capsules including a hydrophobic agent were manufactured on pilot scale capsule manufacturing equipment using Capsugel Lonza proprietary technology to manufacture bi-layer capsules [4].

Disintegration test

Capsugel® Enprotect® or customized capsules were filled with C10 (n=6) and disintegration tests were performed for 2 hrs in HCl 0.1N followed by 1 hr in buffer pH 6.8 using a DT2 disintegrator (Sotax), in accordance with EP pharmacopeia.

Dissolution test

The two-step dissolution was performed by placing unsealed capsules filled with uncoated pellets of Esomeprazole magnesium trihydrate (EMT), an acid sensitive model API in a USP apparatus type II (paddle) for 2 hours in HCl 0.1N followed by 1 hour in phosphate buffer pH 6.8.

Results

Table 1: Compressibility and flowability characteristics of pure C10 and developed formulation (NA=Not Applicable)

Fig 6: Particle size distribution of C10 in (A) number and (B) volume.

Disintegration test

During the disintegration tests of Capsugel® Enprotect® capsules filled with C10, 4/6 showed holes in the capsule shell after 90 min in HCl 0.1N. Disintegration test was performed with C10 and showed that no capsule opened after 2 hrs in HCl 0.1N, Figure 8 B and C.

Dissolution test

Dissolution profiles of custom capsules was compliant EP and USP pharmacopeia, Figure 8 A.

Conclusion

Combination of 70%C10 with 29.5%MCC and 0.5%MgSt presented suitable characteristics to be filled on industrial capsule filling equipment and could serve as pre-mix to enhance oral bioavailability of large molecules. Large quantities of C10 can be encapsulated in customized enteric capsules. Compatibility studies need to be performed on extended duration to confirm the results.

See the full poster on Facilitating encapsulation of permeation enhancers
in customized low water permeability enteric capsules here

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Source: Camille Dumont, Vanessa Gonzalez, Delphine Nombret, Marine Agisson, Vincent Jannin, Capsugel/ Lonza, poster: Facilitating encapsulation of permeation enhancers in customized low water permeability enteric capsules

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