Combo Drugs Require a Complex Design Approach

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Fixed-dose combination drugs formulated with two or more APIs in a single product to improve compliance through simplification of medication needs has been a popular and beneficial lifecycle management strategy. Controlled-release formulations are also a subject of continued interest in the pharmaceutical industry.

“There is a particular focus on creating smarter dosage forms that primarily meet the therapeutic index by maintaining the desired plasma concentrations for extended time periods,” states Deep Patel, a senior formulation scientist with Cambrex. “Reducing the frequency of administration to prolong the duration of effective blood levels increases patient compliance, particularly when API combinations are involved,” he adds. Combining multiple APIs in a single product can create a complex situation, if the actives have varying and/or conflicting properties. Selection of the right excipients can be crucial to the successful development of controlled-release products containing multiple APIs.

Achieving the desired drug-release profile

There are many different types of controlled-release formulations, and one of the first steps must be to establish whether the drug should be formulated as delayed-release, sustained-release, controlled-release, etc., according to Ronak Savla, global scientific affairs manager at Catalent. The next step is to determine the optimal release kinetics (zero order, first order, or pseudo-zero order), after which point the formulator must design a formulation that meets the dissolution (release) profile. Catalent uses physiologically-based pharmacokinetic modeling (PBPK) to determine the optimal desired dissolution rate via construction of a plasma concentration profile.

Establishing in-vitro–in-vivo correlation is still one of the biggest challenges, according to Patel, along with risk management of dose dumping under different gastrointestinal (GI) tract conditions. Designing controlled-release delivery systems for biologic APIs that deliver abuse resistance and meet specific requirements for pediatric dosage forms are also key areas of focus.

Each modified-release dosage form faces both common and unique challenges and requires prototyping to fine-tune the drug release rate and achieve the target pharmacokinetics. “Because modified-release dosage forms contain higher drug loads than immediate-release dosage forms, the potential for dose dumping is a greater concern and must be addressed. API compatibility and stability with excipients must also be assured,” Savla notes. Manufacturing challenges unique to each dosage form include the coating level and drying requirements for coated tablets and multi-layered drug-containing beads and ensuring a homogeneous viscosity and uniform filling of semi-sold fill material incorporated into soft capsules.

Different target patient populations also present different challenges. “Controlled-release formulations are typically solid dosage forms that can be rather large. Patient populations prone to swallowability issues, such as geriatric and pediatric patients, may not be able to swallow the intact dosage forms,” says Savla. For these patient populations, coated beads (or ‘sprinkles’) filled in two-piece capsules are a popular option. The capsule can be opened, and the contents can be mixed with food or certain liquids. Mini-tablets are another attractive option for toddlers and older children. Another consideration for pediatric patients is whether the excipients are acceptable for use in the population.

In addition, because controlled-release formulations typically aim to provide once-daily dosing, the drug must have some colonic absorption, which can be an issue for poorly-soluble APIs. With the increasing prevalence of poorly-soluble drug candidates, the use of solubility-enhancing technologies such as amorphous solid dispersions and lipid-based drug delivery systems are necessary. “Coupling solubility enhancement and modified-release requires the use of a significant quantity of excipients and presents great difficulty to achieve target drug load while retaining a patient-friendly dosage form size,” Savla observes.

Added challenges with multi-API formulations

The critical properties of controlled-release drugs containing two or more APIs include the potential dose differential and varying release profiles for the different drug substances, the stability and compatibility of the APIs with one another and other ingredients in the formulation, and content uniformity, according to Anil Kane, executive director and global head of technology and scientific affairs at Thermo Fisher Scientific. “If the APIs reside within a monolithic tablet or capsule, additional steps may be required to ensure dose uniformity and compatibility and to maintain the target release rate,” agrees Savla.

One of the critical considerations during design of controlled-release formulations containing multiple APIs is the half-lives of each API, which may be different and generally require careful selection of excipients to control each drug release, according to Kane. The dose differential is also important. “Combining a very low dose API (e.g., 1–5 mg) with an API with a high dose (450–550 mg) could be another challenge to controlling the release of each in a specific target site in the GI tract,” he states. The site of absorption of each API may also be different, making it difficult to design a controlled-release strategy for the best clinical efficacy.

The size of fixed-dose combinations (FDCs) formulated as controlled-release products must be considered where swallowability may be an issue, because these dosage forms cannot be split or crushed due to the modified-release functionality. It is prudent, according to Savla, to not create FDCs of two or more APIs with doses in the hundreds of milligrams.

“A promising approach to creating modified-release FDCs in tablet form would be to borrow and learn from formulations containing both immediate-release and modified-release functionalities,” Savla says. He points to multi-layered drugs containing beads, which allow the creation of multiple-release profiles within a single dosage form.

Development strategy is essential

Designing a strategy for development of a controlled-release target product profile is important for many reasons. To achieve this goal, according Kane, a thorough understanding of the pharmacokinetic and pharmacodynamic profile of the small molecule related to its clinical efficacy is needed.

A proper design strategy can have many benefits, including reduction of the frequency of dosing (once-a-day or twice-a-day preparation) and increased safety through avoidance of the possibility of dose dumping. The target patient population may better comply to the medication regimen when consideration is given to the size of the pill to swallow and the time of administration. Another potential benefit is the ability to formulate small-molecule APIs into controlled-release oral solid dosage formats (e.g., tablets, capsules, etc.) or as long-acting sterile injectables.

Crucial role for excipients

The primary role of functional excipients in controlled-release formulations is to modify the release of the drug from the dosage form. There are numerous mechanisms by which these excipients function to release drug, according to Savla: time; pH responsiveness; erosion; osmotic concentration, etc. Controlled-release characteristics can be achieved by the use of polymeric coatings over solid dosage forms such as tablets, capsules, granules, sugar spheres, or ion exchange resins, or alternatively by incorporating polymer matrix systems within solid dosage forms or systems that respond to changes in physical conditions within the formulation, adds Patel.

Excipients used in controlled-release formulations can, according to Patel, also help to overcome the bitter taste of active ingredients or to protect the gastric mucosa. In some cases, these excipients can be used to deter abuse or to help avoid alcohol-induced dumping. In addition, excipients can be used wisely to target the release of the active drug at a specific site of the gastrointestinal tract, behavior that is triggered by pH of the specific region of the GI tract.

“The choice of the right excipient in terms of its properties as well as the right quantity and quality, directly impact the release of the drug in the gut for an oral solid dose controlled-release preparation or in the plasma concentration in the systemic circulation for an injectable form,” says Kane. The level of excipients is critical from a safety aspect as well. Patel adds that proper selection of excipients can help drug product manufacturing through improved flowability, enhanced compressibility, improved bioavailability, and particle size distribution specifically when using different combinations of APIs.

The following categories of excipients and the grade selection are critical in developing an optimal controlled-release formulation, he notes:

• Solubility/permeability enhancers/modifiers

• pH modifiers (to improve stability or release at a targeted region of the gastro intestinal tract)

• Polymers that retard the release the drug based on diffusion, erosion, swelling, etc.

• Excipients/materials that can act as physical barriers.

Savla provides two examples. pH-responsive polymers are a good choice to protect acid-labile APIs from gastric acid or for those APIs that need to reach the colon. Matrix tablets and semi-solid lipids within soft capsules work via erosion and are options for sustained-release delivery.

Pulsatile release polymeric excipients, meanwhile, control the selective delivery (when and where) the API is desired, according to Patel. “These excipients provide a unique advantage due to the timely release that is controlled by coating the drug with selective polymers having sustained or enteric modified-release characteristics,” he observes.

“Overall, the quality and consistency of performance of the excipients, in-vitro as well as in-vivo, are critical to the success of controlled-release dosage forms,” Kane concludes.

Consider excipient variability

While the selection of the excipients with the proper functionality at appropriate levels in the drug product formulation are crucial to drug product performance, a deeper understanding of how variability in the excipients can affect drug product performance is also essential. “Maintaining variability of critical material attributes within an acceptable range is important for a given drug product as excipient concentration and characteristics greatly influence drug product performance with respect to stability, bioavailability, and manufacturability,” Patel notes. In addition, says Kane, development of a control strategy is an important component of improved drug product development.

“A number of drug product recalls identified excipient variability, and therefore a lack of an adequate control strategy, as a contributor to failure of the drug product, further underscoring the need for improved excipient variability understanding,” he observes. To date, however, Kane notes that evaluating the impact of excipient variability on drug product performance has presented a greater challenge than evaluating API and process impacts.

The overall variability in a particular critical quality attribute is a combination of the variability of the API, the excipients, the manufacturing process, and interactions of any of these individual factors, he notes.

“At Thermo Fisher Scientific, we have found that identification of the most impactful material properties is critical to evaluating the effects of excipient variability on drug product performance. This excipient variability understanding can then be combined with the knowledge of each of the API properties and the process parameters used to manufacture the drug product to develop an appropriate control strategy that ensures consistent supply of safe and efficacious drug product,” Kane says.

Experience and expertise are key

In the end, says Kane, the experience of the formulation scientists is the key to developing robust optimized controlled-release formulations that perform consistently in a predictable manner. For controlled-release formulations with multiple APIs, a systematic and well-characterized data set for each of the APIs, along with a scientifically designed strategy for the dosage form and the selection of the right quantity and quality of excipients, are key to successful formulation development. The experience and expertise of the formulator will help to avoid any ‘trial and error’ experimentation and can bring speed to these projects, he concludes.

For Patel, new excipient development is also essential. “The development of excipients that are capable of fulfilling multifunctional roles such as enhancing drug bioavailability and drug stability, as well as controlling the release of the drug according to the therapeutic need, is one of the most important prerequisites for further progress in the design of novel drug delivery systems,” he asserts.

Article Details

Pharmaceutical Technology
Vol. 43, No. 8
August 2019
Pages: 20–22, 45

Citation 

When referring to this article, please cite it as C. Challener, “Combo Drugs Require a Complex Design Approach," Pharmaceutical Technology 43 (8) 2019.