Where does a capsule open? Delayed-release, capsule-in-capsule and liquid fills
A standard hard capsule usually breaks open in the stomach within minutes: in one scintigraphy study, after about 7 minutes on an empty stomach and 11 minutes after food. A delayed-release capsule is designed to release most of its contents in the small intestine instead. A capsule-in-capsule puts a smaller filled capsule inside a larger one, so a liquid and a powder can be kept apart in one dose.
What happens to a standard capsule?
A standard hard capsule is an immediate-release format: its shell softens and breaks open soon after it reaches the stomach. In a gamma scintigraphy study, which follows a swallowed capsule using a small radioactive marker, standard hard gelatin capsules opened after about 7 minutes on average on an empty stomach and about 11 minutes after food (Digenis and colleagues, 2000). Pharmacopoeias check this in the laboratory: the Japanese Pharmacopoeia's disintegration test for capsules runs for 20 minutes.
How does a delayed-release capsule work?
The Japanese Pharmacopoeia describes delayed-release preparations as designed to release most of their contents in the small intestine rather than the stomach, usually with an acid-resistant coating. A capsule can get there in two ways:
- A coating. The finished capsule is coated with a layer that holds up in stomach acid. This adds a manufacturing step.
- An acid-resistant shell. The capsule shell itself resists stomach acid, so no coating step is needed.
Formulators use delayed release for fills that should not sit in stomach acid.
What is a capsule-in-capsule?
A capsule-in-capsule puts a smaller, pre-filled capsule inside a larger one. Each capsule holds its own fill, so ingredients that would not stay stable together, or that come in different forms, can travel in one dose. Two laboratory studies used it this way:
- A liquid and a powder kept apart. Researchers put a powder in a small inner capsule and an oil-based liquid in the outer capsule, so the powder did not break down in the liquid (Shahba and colleagues, 2022).
- Two release times in one dose. An acid-resistant inner capsule delayed the release of one ingredient while the outer capsule released the other straight away (Althobaiti and colleagues, 2023).
Can a hard capsule hold a liquid?
Yes. Oils and semi-solid fills can go into hard capsules, which are then sealed so they do not leak (Niederquell and Kuentz, 2011; Tyagi and colleagues, 2013). Fill volume and filling temperature both matter, so liquid fills are trialled on the line before production.
| Format | Opens | Typical use |
|---|---|---|
| Standard capsule | In the stomach, within minutes | Powders and most everyday fills |
| Delayed-release capsule | Mainly in the small intestine | Fills that should not sit in stomach acid |
| Liquid-filled hard capsule | In the stomach, once sealed and swallowed | Oils and liquid ingredients |
| Capsule-in-capsule | Each capsule on its own schedule | A liquid with a powder, or two release times |
Building a new formula around Athemin®
Athemin® is supplied as a liquid. In a capsule it can be the fill of a sealed hard capsule, or sit in one capsule of a capsule-in-capsule while a powder sits in the other. That lets you combine Athemin® with other ingredients in a single dose, in a product built for your own audience.
We start from your brief: who the product is for, how many capsules a day they will take, the market you sell in and your target price. From there we choose the fills, the shell and the release format, then trial it with you before you commit. Which ingredients can go in, and what the label can say, follow the rules of the market you sell in.
What does the format change on your label?
The release format does not change the rules on what your label can say. In Malaysia, health supplements in forms such as capsules, tablets, powders and liquids are registered with NPRA, and the Drug Control Authority decides each application. Read Does my product need NPRA registration? before you choose.
Sources
- Digenis GA, Sandefer EP, Page RC, et al. Bioequivalence study of stressed and nonstressed hard gelatin capsules using amoxicillin as a drug marker and gamma scintigraphy. Pharm Res 2000; 17(5): 572 to 582 (mean in vivo opening times). PubMed 10888309
- The Japanese Pharmacopoeia, 18th edition, English version, Ministry of Health, Labour and Welfare: General Rules for Preparations (delayed-release preparations) and general test 6.09, Disintegration Test (20 minutes for capsules). mhlw.go.jp
- Shahba AA, Sherif AY, Elzayat EM, Kazi M. Combined ramipril and black seed oil dosage forms using bioactive self-nanoemulsifying drug delivery systems. Pharmaceuticals 2022; 15(9): 1120 (powder in an inner capsule, liquid in the outer). PMC9503356
- Althobaiti AA, Ashour EA, Almotairy A, et al. Development and characterization of different dosage forms of nifedipine/indomethacin fixed-dose combinations. J Drug Deliv Sci Technol 2023; 80: 104117 (acid-resistant inner capsule, immediate-release outer capsule). PMC9897319
- Niederquell A, Kuentz M. Introduction of a theoretical splashing degree to assess the performance of low-viscosity oils in filling of capsules. AAPS PharmSciTech 2011; 12(1): 323 to 330. PubMed 21286883
- Tyagi VK, Singh D, Pathak K. Semisolid matrix-filled hard gelatin capsules for rapid dissolution of amlodipine besilate. J Adv Pharm Technol Res 2013; 4(1): 42 to 49. PMC3645358
- NPRA, Health supplements (registration of capsules, tablets, powders and liquids; Drug Control Authority decision). npra.gov.my