For oral dosage forms, “onset of action” is defined as the duration of time between oral administration of the active ingredient, which can either be a drug or nutraceutical and its therapeutic effects on the patient. It typically ranges from just a few minutes to over one hour, depending on the dosage form and individual characteristics of the active ingredient in question.
The therapeutic effect can only occur once the active ingredient that will promote this effect has been fully solubilized in the stomach of the patient and has entered his or her bloodstream.
Therefore, solid oral dosage forms that are based on a solution of an active ingredient, such as soft capsules, will provide a faster onset of action compared to oral tablets and capsules where active ingredients are in powder form and need to be solubilized in the patient’s stomach after the disintegration of the tablets or the shell rupture and solubilization of the capsules.
Soft Capsules: Solid Oral Dosage Form That Promotes Rapid Onset Of Action
Compared to other oral solid dosage forms, soft capsules or softgels that contain a liquid formulation of the active pharmaceutical or nutraceutical ingredients, can provide the following important clinical benefits:
- Faster onset of action: soft capsules contain liquid fill where the drug or nutraceutical ingredient has already been solubilized, so the ingredient solubilization step that occurs in the stomach is not necessary as in the case of tablets and hard capsules that are filled with powders. Before dissolution, tablets also need to disintegrate in aqueous stomach fluids which leads to a relatively slow onset of action.
- Optimized drug bioavailability: when formulated in tablets or hard capsules, some of the active pharmaceutical ingredients or nutritional supplements demonstrate impaired bioavailability that can result in low efficacy and reduced therapeutic effects.
Besides this, the outcome of several consumer preference surveys has confirmed that clear softgels are the preferred administration form of medicines and nutritional supplements. This is because they are considered easy to swallow and are perceived as easy to digest, fast-acting, and effective.
Gelatin: A Natural Excipient Of Choice For Soft Capsules
Gelatin offers a broad spectrum of qualities that make it a natural choice for soft caps. It is universally well-tolerated and its unique technological and biopharmaceutical properties mean that it is a versatile excipient with excellent biocompatibility. The gelatin used for pharmaceutical or nutraceutical soft capsule products is described by the official pharmacopeias.
From the production perspective, gelatin presents an unrivaled machinability and it is also thermoreversible, which makes it the excipient of choice for soft capsules.
However, soft gelatin capsules face a major challenge in the form of crosslinking. This is a natural phenomenon that occurs in gelatin and causes a longer dissolution time of the capsules’ shell, a slower rate of drug release, and reduces both the stability and shelf life of the final product.
Gelatin Crosslinking: A Natural Phenomenon That Affects Gelatin Solubility
The formation of intermolecular covalent bonds between two or more gelatin molecules is called crosslinking.
Gelatin crosslinking leads to the formation of big polymeric gelatin chains that have reduced solubility. Deceleration and the reduction of solubility of the shell of gelatin capsules promote a slower capsule rupture and dissolution rate, which affects both the stability and fill release of the products.
This process can be induced via the following different routes:
- Chemically: caused by chemical crosslinkers or enzyme catalysis
- Thermally: exposure to high temperature (T >30°C, relative humidity (RH) >60%)
- Physically: mechanical agitation or photooxidative exposure
Chemical Crosslinking: The Main Responsible Route
As a protein, gelatin has several reactive side groups, such as carboxylic, hydroxyl, and amino groups.
Substances that are chemically classified as aldehydes, polyphenols, carbohydrates, metal ions, etc. seamlessly interact with the reactive groups of gelatin, which promotes the formation of firm covalent bonds.
These chemical interactions can occur between the capsule shell and liquid fill where the covalent bonds can be formed via the interaction of:
- Gelatin and APIs (active pharmaceutical ingredients)
- Gelatin and nutraceutical ingredients
- Gelatin and solvents used for the solubilization of ingredients
Active Ingredients That Promote Crosslinking
The best-known compounds that induce crosslinking reactions with gelatin protein chains are aldehydes. These typically form a crosslink with amino groups of gelatin (e.g. arginine or ε-amino of lysine) via an imine intermediate.
A significant number of OTC drugs and nutritional supplements for which the action in the organism of the patient needs to be fast are formulated as soft capsules. This is due to the rapid onset of action that this oral dosage form promotes.
However, some of these active ingredients are known as important crosslinkers, or the solvents that are used for their solubilization (such as polyethylene glycol, polyvinyl acetate phthalate, povidone, etc.), can promote crosslinking.
Painkillers, antihistaminic drugs, antipyretics, as well as drugs and supplements that are used as digestive aids or to reduce abdominal discomfort, among other things, need to act in both a fast and efficient way. To that end, patients and consumers are willing to pay a higher price for those products that will promote fast or immediate relief of related problems.
Listed in Table 1 are some of the widely used pharmaceutical and nutraceutical ingredients that are expected to have a rapid onset of action and their respective main therapeutic use, and which are related to crosslinking due to their chemical structure or the need to use solvents that cause cross-linking.
As metal ions and oxidizing agents also cause crosslinking, minerals (ex. zinc, iron) and some vitamins (ex. vitamin C, K2) are also considered crosslinkers.
Solution For Reduced Crosslinking, Fast Dissolution, And Rapid Onset Of Action
At PB Leiner we aimed to solve this important issue and assist soft capsule producers in delivering to their markets products that have fast dissolution, rapid and reliable fill release, with improved stability and increased shelf life of their final dosage formulations. PB Leiner has achieved this by developing a gelwoRx™ Dsolve portfolio – a range of special gelatin products that do not contain any additives.
To prove the efficiency of the gelwoRx™ Dsolve portfolio, multiple tests were conducted on the pilot production of soft capsules to evaluate their stability and dissolution.
These soft capsules were submitted to chemical crosslinking by adding an important amount of crosslinkers in the capsule fill. In the sequence, they were subjected to thermal crosslinking by exposing them to a high external temperature of 40°C and high relative humidity of 75% for a period of six months.
The results obtained at six months (6M) confirmed that gelwoRx™ Dsolve products significantly outperform the standard soft capsules gelatin in terms of dissolution.
Conclusion
For solid oral drug or nutritional supplement products for which the rapid onset of action is paramount, soft capsules are the oral form of choice.
Gelatin, which is the most adequate excipient for soft capsules, can present physical crosslinking due to exposure to high temperatures and high relative humidity. Furthermore, it can present chemical crosslinking via interaction with the liquid fill of the capsules. Therefore, to ensure fast capsule dissolution and the rapid onset of the drug’s action, the use of a special gelatin product in soft capsules is highly indicated.
PB Leiner’s gelwoRx™ Dsolve portfolio is a group of products that present significantly lower crosslinking tendency in the presence of crosslinkers compared to standard soft caps gelatin. The gelwoRx™ Dsolve portfolio has been specially developed to solve this common issue and assure fast dissolution and rapid and reliable fill release with improved stability and increased shelf life of your final dosage formulations.
Author Details
Jelena Cvijic, MSc in Pharmacy- Global Product Manager Pharma, PB Leiner
Publication Details
This article appeared in Tablets and Capsules Magazine: Vol. 22, No. 3May/June Sourcebook 2024Pages: 12-15