(M1130-03-16) Enteric Functional Ready-to-Fill Capsule Solution from Pre-Clinic to Commercial

Purpose: With introduction of newer technologies such as mRNA, large molecules, and fast-track approval system from regulatory bodies, there is a need to revisit oral drug delivery system for such new molecules by means of gastro-intestinal drug release modulation to improve bioavailability, stability of the molecule, provide site specific drug delivery and prevent drug in-vivo instability before absorption. While injection routes of administration are preferred for such drugs, oral drug delivery presents simplicity in dosing regimen and patient acceptance. One of the major steps in designing such drug formulations starts from preclinical stage. A convenient option for testing drug pharmacokinetics is capsules designed for small animal testing. Currently, preclinical scientist depends on immediate release capsules or liquid formulations such as oral solution or suspension to dose the animals. However, if drugs have instability problems and require enteric protection, this puts additional time and efforts to develop a formulation. This becomes more complicated due to minimal availability of drug for testing as well as instability of drugs to moisture, solvents, or heat, making unit operations leading up to enteric coating of the dosage forms, difficult. The purpose of this work is to introduce a special enteric coated capsule for preclinical application testing in small animals and comparing it with commercial enteric coated capsule for human clinical testing, in terms of drug release, functionality, speed and simplicity to develop an enteric formulation for challenging drugs. Data is shown for a surrogate drug molecule to validate proof of concept. Additional stability testing is underway.

Methods: Pre-locked, Size 9h hard gelatin capsules from Torpac^® and Size 0 HPMC capsules from K-CAPS^® were utilized for this study. Empty capsules were coated with a proprietary combination of methacrylate polymer chemistries to a specific weight gain based on their surface area. These ready-to-fill, enteric capsules were compatible with standard filling equipment, and required no banding or additional downstream processing. Caffeine was used as a surrogate drug to validate proof of concept. Coating performance was evaluated via a two-stage disintegration test, two-stage dissolution test, and acid resistance test. Caffeine: lactose blends were filled into enteric coated, size 9h and size 0 capsules based on their respective volumes. Disintegration tests were performed in 0.1 N HCl for 2 h followed by pH 6.8 potassium phosphate monobasic buffer for 2 h. Dissolution tests were performed in USP Type I apparatus at 37 °C, size 40 mesh, with a basket speed of 75 rpm; filled capsules were exposed to 0.1 N HCl media for 2 hours followed by pH 6.8 potassium phosphate monobasic buffer. A blend of hydroxy naphthol blue dye/MCC was used as indicator for the acid resistance test. Upon exposure to acid, hydroxy naphthol blue instantly changes color to pink, providing a visual indication of enteric performance; capsules were observed for visual changes during the disintegration testing in 0.1 N HCl for up to 4 h.

Results: The disintegration and dissolution tests demonstrated that both size 0 and 9h enteric capsules remained intact in 0.1 N HCl (for up to 2 hours) followed by complete and fast release of caffeine upon changing the media to pH 6.8 potassium phosphate monobasic buffer (Image 1). This behavior was further confirmed through the acid resistance test wherein the capsules did not bleed pink color in 0.1 N HCl even after four hours. Upon opening, the capsule contents stayed intact without any color change assuring complete content protection (Image 2). Both sizes of capsules showed identical enteric protection performance with low variability.

Conclusion: This study demonstrated robust performance of ready-to-use enteric size 9h and size 0 capsules, showing strong acidic protection in 0.1 N HCl for up to 2 hours followed by immediate drug release at pH 6.8. Hence, this capsule platform offers a potential solution to deliver drug candidates to different regions in GI tract right from discovery stage to commercial stage with consistent PK performance. It provides a promising approach to deliver different drug candidates such as mRNA, proteins, peptides, microbiomes and other sensitive agents to different regions in GI tract in different capsule sizes, at a lower cost-accelerating time to market.

Image 1: Dissolution results for size 9h and size 0 enteric coated capsules filled with caffeine and lactose powder blend

Image 2: Illustration of acid resistance test results for uncoated or enteric coated size 0 capsules filled with hydroxy naphthol blue and MCC powder blend