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The challenge of achieving sustained delivery of an active ingredient or nutrient can be achieved with extended-release formulations.
To effectively treat many conditions, it is beneficial for the API or nutrient to be slowly released from the dosage form over a prolonged period of time. Take the treatment of magnesium deficiency, for example. Magnesium is an essential mineral that is important for many vital functions. Magnesium deficiency has been linked to a range of conditions, including diabetes, metabolic syndrome, and coronary artery disease (1). Despite its importance, many individuals do not receive sufficient amounts in their diet. Certain populations, such as athletes and pregnant women, also have an increased need. As a result, supplements are taken to boost magnesium levels.
To be most effective, dosing of this important nutrient should be intelligently managed. The body is able to absorb more magnesium when it is supplied as a steady stream rather than as a large single burst. Any excess magnesium that is taken but not absorbed is simply excreted from the body. One approach to dosing a regular supply of magnesium is to take multiple, immediate-release dosage forms at regular intervals throughout the day. This can be inconvenient, however, and lead to poor compliance to dosing routines.
With individuals increasingly expecting convenience in all areas of their lives, the requirement to carry with them and remember to take multiple doses of a nutraceutical product simply does not meet their needs.
So how can sustained delivery of an active ingredient or nutrient be achieved over extended periods of time, while ensuring products are user friendly?
For many developers, the solution to this challenge is extended-release formulations that steadily deliver the active ingredient or nutrient to the body over a certain period of time. A single dose of an extended-release formulation can successfully achieve sustained blood plasma concentrations at levels that would otherwise require multiple immediate-release doses.
There are a number of options available when developing extended-release formulations. One fundamental way of prolonging the release profile of a product is through chemical modification of the API using a poorly soluble salt. This approach is essentially counter to the traditional strategy of improving the bioavailability characteristics of a pharmaceutical or nutraceutical product by selecting a highly soluble ion pair combination. Another relatively straightforward approach is to decrease the rate of dissolution by reducing the surface area of the API. This can be achieved by using large crystals instead of small or micronized particles. While these approaches can be effective for some products, for longer-release profiles, more sophisticated technologies are required.
An alternative means of controlling the release of APIs or nutrients where more extended-release profiles are required is the use of various formulation strategies. One of the common approaches is the use of matrix systems, which involve mixing and compressing the API or nutraceutical ingredient with a gelling or swelling excipient that slows the rate of dissolution. Various matrices can be used, including hydrophilic or hydrophobic polymers or lipid excipients.
Another strategy for developing extended-release products is the use of osmotic pump formulations. These take the form of a tablet or capsule consisting of an API-containing core surrounded by a semi-permeable membrane into which one or more holes have been laser-drilled. As the formulation absorbs water and swells, the API is slowly forced out of the hole by osmotic pressure. While these dosage forms are more tolerant of variations in gastrointestinal conditions and are capable of delivering very consistent results, they are often cost-prohibitive to use for most over-the-counter products, such as nutraceuticals.
An effective and more affordable approach for developing extended-release products is the use of coating technologies. Through the careful selection of appropriate coating agents, the rate of dissolution of the nutrient can be controlled, facilitating immediate, extended, or even delayed release depending on the requirements of the product.
The traditional coating approach involves using a solution of the API and excipients to coat a seed particle using a fluid bed process. However, a major limitation is the fact that coated particles must be dried, requiring large amounts of time and heat, particularly when the solvent is water. Additionally, multiple coating layers must typically be applied, adding time and cost to manufacturing cycles. As a result, alternative coating technologies have been developed.
Hot melt coating (HMC) is an alternative technology that is better suited to the manufacture of extended-release formulations. HMC involves coating particles of the API or nutrient with a layer of lipid excipient (see Figure 1).
During manufacture, the seed particles are suspended in a fluid bed coater, while molten excipients are sprayed onto them using a heated nozzle. As the seed particles are maintained at a lower temperature than the melting point of the excipient mix, the molten droplets wet the particles and solidify upon contact, resulting in a homogeneous coating layer.
Because no solvent is involved, the process is rapid, typically taking less than two hours for commercial batch sizes. Furthermore, once process parameters have been optimized, no curing or sintering effects are typically encountered, and undesirable side effects, such as agglomeration, are greatly minimized. Through the addition of appropriate emulsifiers to the excipient mix, the rate of dissolution can be adjusted to meet the product’s requirements.
HMC is applicable to a wide range of oral dosage forms, including multi-layer tablets, multiple unit pellet systems, and hard gelatin capsules. However, when used to create extended-release products, these formulations can be problematic. As extended-release formulations usually have a higher dosage than immediate release products, traditional tablets and capsules must often take a larger form, which can present swallowing difficulties for many people. To overcome this, many individuals resort to crushing, dissolving, or chewing their tablets (and some do not take them at all) (2). These approaches can break down the extended-release mechanism and result in the delivery of a single large dose, with potentially dangerous health consequences.
HMC can be used to manufacture orally disintegrating granules (ODGs), however-a dosage form that overcomes many of the challenges associated with conventional tablets and capsules. ODGs are ideal for extended-release products as they allow a large dose of up to 3000 mg to be delivered in the form of small particles in a single “stick pack”. ODGs are poured directly into the mouth and can be easily swallowed without the addition of water. Moreover, as the same coated particles can be used to formulate different finished products (such as those with different dosages or flavors), the combination of HMC and ODGs offers producing a broad product range.
Controlling the rate of release of the nutrient and ensuring that product met the expectations of modern consumers were important factors to address when developing a magnesium formulation on behalf of a customer. After considering the options, ODGs manufactured using HMC offered the ideal solution. This combination ensured extended-release of magnesium, while the dosage form could be swallowed easily and had a pleasant taste and mouthfeel.
Figure 2 compares the release profile of the extended-release formulation containing 85% magnesium oxide against the uncoated raw material. The raw material completely dissolved within two hours, whereas the coated material only released approximately 45% of the nutrient over the same time period. Even after 16 hours, just 70% of the nutrient was released, demonstrating the formulation’s ability to release magnesium oxide over a prolonged period. These extended-release characteristics could be adjusted by simply varying the amount of coating or by using different coating materials.
The stability of the product was also an important design factor. Figure 2 shows the release profile of the product stored for a period of 12 months at 25 °C and 60% relative humidity. The dissolution profile of this product was very similar to that measured at the initial time point, indicating the stability of the formulation. Importantly, the extended-release profile was maintained, indicating that long-term storage (climatic zone 2) conditions did not affect the product’s ability to deliver magnesium over a sustained period.
Pharmaceutical and nutraceutical companies are often faced with the task of developing dosage forms that produce an effective blood plasma concentration of the (active) ingredient over a prolonged period of time, while delivering a convenient and user-friendly experience for consumers. Extended-release formulations based on the use of orally disintegrating granules and hot melt coating can be an effective solution to this development challenge.
This approach allows developers to tune the release profile to meet the needs of the product, and offers a cost-effective means of establishing a broad product range comprising multiple dosages and flavors. By overcoming the swallowing challenges associated with large dosage forms and offering enhanced taste and mouthfeel, these user-friendly extended-release formulations can help to deliver the pleasant oral experience that modern consumers have come to expect.
1. M. Shechter, et al., Magnes Res 25 (1) 28–39 (2012).
2. Hermes Pharma, “A Hard Truth to Swallow?” www.swallowingtablets.com, accessed Jul. 25, 2018.
Vol. 43, No. 2
When referring to this article, please cite it as M. Koeberle, “A User-Friendly Approach to Developing an Extended-Release Product," Pharmaceutical Technology 43 (2) 2019.
Martin Koeberle is head of Analytical Development & Stability Testing, HERMES PHARMA-a division of Hermes Arzneimittel GmbH.