Torkel Gren is senior director, Technology Officer & Strategic Investments at Recipharm.

Torkel Gren

Modified release (MR) has been one of the fastest growing dosage forms in recent years, and this growth shows no sign of slowing down. In fact, according to a December 2020 study, the global MR market, including oral solid dose, is expected to reach $59.7 billion by 2025, up from $44.5 billion in 2019, growing at a compound annual growth rate of 7.6% (1).

The ability to control the rate or even the site of release of the API is one of the key reasons why MR is becoming increasingly popular.Unlike immediate-release (IR) formulations, which provide a rapid effect, MR dosage forms can extend the time the medicine remains active, or drug release until a drug reaches a specific area. 

There are several different ways to achieve MR. One such way is to develop a multiple unit formulation. These consist of coated pellets of APIs combined within a capsule—or a tablet.

MR can also be achieved using matrix tablets—where the API is homogeneously dispersed in an insoluble or gelling excipient. They may also consist of a tablet coated with a release-controlling polymer. 

Various types of coatings are available, such as those that are not dissolved but allow a slow diffusion, which are suitable for prolonged release. pH-sensitive or time-controlled polymer coatings are used for delayed release and, by using different combinations of coating materials, developers can effectively achieve a wide range of release profiles. 

As a result of the ability to control a medicine’s release profile, MR products can achieve clinical objectives beyond those of a conventional formulation with the same drug because the effect of a drug substance is usually proportional to its concentration in blood plasma. By modifying the release rate, the plasma concentration can be controlled over time (2,3). Consequently, the effect over time can be tailored for optimal effect. Moreover, the balance between effect and side effect can be optimized.

By prolonging or delaying release of the API, MR technology can have severalpositive impacts. In addition to extending duration and the resulting therapeutic effect of active ingredients, MR can also help to reduce adverse side effects by lowering the peak drug concentrations in the blood.

Using enteric coatings, developers can protect acid-sensitive drugs as they pass through the stomach to delay release of the API until it reaches the intestines. This delayed-release capability means that APIs, which would otherwise be degraded in the low pH of the stomach, can be administered orally. Furthermore, by delaying the release of the API, it is possible to avoid unpleasant side effects due to irritation of the stomach.

In addition, MR technology can be used in conjunction with fixed dose combination (FDC) technology to create more effective multi-API products. In particular, multiple-unit formulations are suitable for FDC.

The unique capabilities offered by MR dosage forms ultimately provide a number of benefits for patients. By prolonging the release of an API and combining multiple APIs into a single dose, the number of times a patient needs to take a dose can be reduced, as well as the number of tablets or capsules at each timepoint, enhancing useability and, in turn, boosting patient adherence.

MR products offer benefits for manufacturers too. As well as optimizing the effectiveness of new APIs, they can be used to enhance the performance of existing APIs. For instance, MR formulations can be used by drug developers to improve the bioavailability or the duration of blood concentrations of the API compared with the original product. 

As a result, MR technology can help extend the profitable lifecycle of well-established products, for example, by obtaining new market exclusivities, with positive effects on a company’s revenue.

However, developing MR drug products can also be challenging for pharma companies without the right expertise. Failing to understand the API, the target product profile (TPP), and the development process required could lead to costly delays in development, undermining return on investment.

There are several challenges that need to be addressed to successfully develop effective MR dosage forms. For example, it is extremely important to guarantee patient safety by ensuring the correct release rate. This release rate must also be maintained over time, throughout the shelf life of the product. Hence, above all else, the process parameters that are critical for release rate have to be identified and controlled from the start of the product development process.

The quality of the excipients used in the formulation can have a strong impact on release rate, so considerable investigation is needed to understand the precise effect. This investigation is crucial to devise the right specifications for the chosen excipient.

In particular, the quality of polymeric excipients must be controlled. The release-controlling effect of polymers will depend on a number of characteristics, such as degree of substitution, molecular weight, and molecular weight distribution. Even small variations can have significant effects on the release rate, so it is important to establish raw material specifications that ensure correct release rate. The effect of the presence of plasticizers must also be considered.

Achieving and maintaining the release rate can be particularly challenging when using MR technology for FDC drugs because it is often necessary to ensure that the chosen technology maintains multiple release rates—one for each API—which can be difficult to achieve. Developers also need to consider the potential interactions between APIs and the impact of the excipients on each of the active ingredients being used. For both these challenges, the use of coated pellet technology can be useful as the APIs can be separated into different pellets. 

Another key challenge is to develop the analytical methods that are needed for quality control. Methods have to be developed to analyze the product’s 

 dissolution rate as well as its identity, assay, and degradation products. For FDC products, these methods need to work for all APIs included within the product.

Quality control adds significantly to the cost of goods for pharmaceutical products. To reduce the time needed for quality control and, hence, limit manufacturing costs for FDC products, it is recommended to, if possible, develop one single method that is capable of reviewing all APIs. The reason being, running two separate methods to assess two compounds, instead of assessing them by one method, will take double the time in the analytical lab.

In most cases, a chromatographic method is preferred. This method needs to be suitable for routine analysis and be effective for all of the drug substances in the products. This task can often be challenging, and expert analytical support is recommended to devise the most efficient and effective solution.

There are different MR technologies that are suitable for different drug substances in different circumstances. For example, hydrophilic matrix tablet technology can be harnessed to create effective MR tablets.

By ensuring the API is evenly spread throughout the tablet together with a suitable polymer, it is possible to control and prolong the release of the active ingredient. A suitable enteric coating can further delay release until after the tablet has passed through the stomach.

Matrix tablets require a relatively straightforward manufacturing process,helping to minimize the cost of production for drug developers. This reduced production cost in turn lowers the cost of the finished product for patients or healthcare providers.

However, matrix tablets are difficult to use for FDC, as the release of each drug cannot be controlled independently and, as such, there is a risk of incompatibilities.

In these cases, drug developers can use pellet technology—or multiple unit formulations—to create their MR products. Multiple unit preparations are more complicated to produce than standard monolithic formulations. Nevertheless, they have considerable advantages from both a therapeutic and a manufacturing perspective. 

For instance, they offer less variable progression in the digestive system and can be used to combine components with different release profiles. When housed in a capsule, pellets can allow the modification of a dose without the need for reformulation—simply adjust the number of pellets in the capsule to change the dosage and add coatings to control the rate of release. 

Pellets are also versatile because they can be filled into capsules or sachets, compressed into tablets, or even dispersed in a liquid suspension, catering to the varying administration needs of patients.

In addition, by allowing the combination of several types of pellets in a single FDC dosage form, pellets can lower the cost of manufacturing significantly compared to the cost of producing separate products to be administered concurrently (3). It also lowers packaging and logistics costs.

The choice of technology will depend on the nature of the API, the indication, and the operational needs of the drug developer. Selecting the right technology is essential to ensure successful MR drug development. With this in mind, it is crucial to work with expert partners that have experience of working with MR dosage forms.

For efficient development, a cross-functional team is vital, incorporating formulation scientists with specific MR expertise, as well as analytical chemists. Quality assurance and manufacturing experts are also essential if a MR development project is to be a success.

It can be expensive and time-consuming to acquire all of these varied skillsets within an in-house team. However, there are outsourcing partners that already have the MR experience and the required infrastructure to deliver comprehensive and time-efficient MR development.

Partners with extensive experience in both coated pellet technology and matrix tablet technology are ideal to meet the needs of drug developers and can support customers in choosing the most suitable MR solution for their needs, enhancing flexibility and customisations of the development process. Of course, it is also important that a partner can manage scale up and tech transfer into efficient routine production.

Many contract development and manufacturing organisations (CDMOs) are engaged in significant innovation in the MR field, including developing new technologies capable of combining several drug substances with different release profiles. Some are even devising capsule products that comprise both minitablets and pellets. These technologies further enhance the ability to control the release of APIs, to onset the desired therapeutic effect and the ability to combine multiple APIs in one product.

Such CDMOs are well placed to support drug developers to successfully bring new MR drugs to market in a reduced timeframe, so patients can benefit from better treatments to improve their health.

The rise of MR drugs shows no sign of slowing. Their unique benefits when it comes to improving the effectiveness of drugs and improving the patient experience mean MR drugs will continue to be an attractive option for drug developers.

The development and manufacturing challenges they pose can be daunting for developers but, with access to the right expertise, MR can be an effective and inexpensive route to a new product.

MR is ideal for the reformulation of existing medications to achieve therapeutic improvements or extend patent lifecycles. It may even be a necessity for some new chemical entities (NCEs)—particularly those that are sensitive to acid degradation, where oral bioavailability would be especially low without the use of delayed release.

By working with MR specialists, drug developers can overcome any barriers to development they may face. They can be confident they have the tools they need to deliver MR innovations effectively.

Global Controlled Release Drug Delivery Market 2020 by Company, Regions, Type, and Application, Forecast to 2025

, Research Report, June 28, 2020.
2. M. Rowland and T.N. Tozer, 

Clinical Pharmacokinetics—Concepts and Applications

, pp. 93–97 (Lea & Febiger, 2nd Ed, 1989).
3. EMA, 

Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms

Articles

Modified-release dosage forms present new opportunities for drug developers and can help overcome challenges, such as short biological half-life or poor bioavailability due to degradation in the stomach. 