One of the goals of any oral formulation development project is to create a formulation in which the active pharmaceutical ingredient (API) is sufficiently bioavailable to have the desired therapeutic effect. This is a huge area of focus for formulators as a result of the drug industry’s interest in turning poorly soluble compounds into products.¹

However, while ensuring the API is appropriately bioavailable remains the main driver of innovation in formulation development, other factors are growing in importance.

Patient demand is an increasingly important consideration. Patients want medicines that are convenient to take and safe, which is forcing the drug industry to develop, for example, tablets that combine several APIs. Likewise, significant therapeutic advantages, such as longer duration and lower plasma peak levels, can be achieved by creating modified release products using existing APIs.

In addition, innovations in excipients as well as advances in processing and manufacturing technologies are impacting formulation development. Demands for safer and more consistent drug products are shaping how formulators approach the creation of new products.

Finally, regulatory demands for safer, more efficacious products are feeding into formulation development, particularly in areas like abuse deterrence.

Early phase formulations: Stability and bioavailability
Many first-in-human trials use liquid formulations of drug candidates on the basis they are faster and cheaper to develop and allow for the dose to be varied, which is often required during Phase I clinical studies. Moreover, liquid formulations are often seen as a way to maximize oral bioavailability even though they are usually not suited to commercialization. The thinking is that, if a candidate continues to show promise during Phase I, there will be enough time to reformulate for later stage studies.

While this strategy is still valid, there is a growing body of opinion that the ability to develop a future solid product should be carefully considered during the development of formulations for Phase I trials. In particular, two specific attributes—stability and bioavailability—should be taken into consideration. The rationale is that paying attention to these characteristics at the earliest possible stage allows for better informed go/no-go development decisions, which let pharmaceutical companies make most effective use of their R&D budgets. In addition, any useful stability and bioavailability data may save time later by helping to shape the development of formulations for later phase trials and commercialization.

Inhalation products
Inhalation is another major focus for formulation development at present. In particular, it is used for local treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Here, local treatment reduces the risk of side effects due to low systemic exposure. Drugs delivered via the lungs may also give a faster onset of action.
The challenge for researchers is that developing an effective formulation that can be inhaled safely is a highly complex and technically challenging process that involves working with factors such as choice of excipients, particle size distribution and delivery device.

The formulation challenges vary depending on which type of delivery device is used. Attributes critical to effective delivery of a solution using a metered dose inhaler—droplet size and viscosity for example—are defined by the formulation. Likewise, for a drug administered using a dry powder inhaler, particle engineering is required to ensure that the APIs and excipients achieve the correct dispersion when inhaled.

Another major challenge facing developers of inhalable drugs is to create a formulation that is safe and effective, even if the delivery device is used incorrectly.²

Combination products
The growing market for fixed dose drug combination (FDC) products that contain two or more APIs is also shaping innovation in formulation development. Physician and patient desire to reduce the number of doses they take for convenience and to increase compliance is increasing demand for combination products.³

The challenge of combining two APIs in a single formulation is significant. The aim is to ensure that the respective ingredients are stable and behave appropriately from a pharmacokinetic and pharmacodynamics standpoint.⁴ In addition, ensuring uniformity of distribution and preventing drug-drug interactions using techniques like layering, pellets or mini-tablets are vital.

Modified release formulations
Demand for modified release drugs is also impacting formulation development. Modified release products may achieve sustained concentration in the blood plasma and have reduced toxicity. Drug release can be directed to the gut rather than the stomach to avoid degradation of the API or irritation of the gastric bladder. Consequently, modified release technology is very useful in the development of drug products for new chemical entities (NCEs) as well as in life cycle management and repositioning of existing drugs.

There are two main drivers of demand for these products. First, significant therapeutic advantages can be achieved by medicines whose effects are sustained for several hours, thereby minimizing the number of tablets or capsules required and reducing the risk that the patient will forget to take the prescribed medicine.  In some cases, the lower peak plasma concentrations resulting from modified release preparations also give reduced side effects.

The second main driver is generic competition. It has become commonplace for pharmaceutical companies whose products face impending patent loss to develop modified release versions of the same product. The idea is that these reformulated versions of existing products have improved characteristics that will attract patients and help the innovator company to stave off generic competition and maintain market share for as long as possible.⁵

The impact on the formulation development has been an increased demand for technologies that can control the release of APIs, either those that ensure stable release over a sustained period, release in specific organs or those that delay release. As a result, multi-particulate formulations, which are composed of pellets, have experienced a surge in popularity in recent years.⁶

Abuse deterrence
Growing concerns about prescription drug abuse, particularly involving opioids,⁷ are also influencing formulation development. Regulators in the U.S., Europe and elsewhere^8,9 advise pharmaceutical firms developing certain types of products to include technologies that will prevent them being abused.

This recommendation has prompted the development of a variety of technologies that, for example, prevent tablets from being crushed, melted or manipulated in such a way that the API is released. Which of these technologies is most appropriate depends on the drug. For example, some stop tablets from being dissolved in alcohol, while others prevent them releasing their actives as a result of physical manipulation.

Pediatric formulations
Children have different medication needs. They need smaller doses and small children are not able to swallow tablets or capsules. These problems have been obvious for a long time and in recent years there has been an increasing pressure to make sure that drugs are available in products that are suitable for administration to children. Here liquid dosage forms can be of great value as they are easy to swallow and can be easily adjusted for differences in body weight.

Unfortunately, liquid dosage forms are associated with several problems such as unpleasant taste and poor stability. An unpleasant taste is relatively easy to hide in a tablet or a capsule but will be revealed by a liquid formulation unless it is formulated in order to mask it. In many cases it may be very difficult to hide the unpleasant taste completely, which may cause significant problems in making young patients adhere to the prescribed dosing. However, it should be the goal to mitigate any taste problems as far as possible.
Careful formulation development will also be needed to ensure acceptable shelf life. This may also be improved using so called dry syrups i.e. dry powder or granules in a bottle which is diluted (reconstituted) prior to use.

Large molecule drugs
The pharmaceutical industry’s change of focus from small molecule products to large molecule products synthesized in biological systems is also influencing formulation development. At present the vast majority of large molecule drugs—protein therapeutics, vaccines, etc.—are delivered by injection.

Both industry and patients recognize that injections are not ideal, which has prompted considerable interest in developing more convenient means of delivering large molecule drugs. Much of the focus has been on the use of auto-injectors that allow the patient to self-administer rather than relying on a physician. A more challenging alternative would be to avoid the injection in favor of other more convenient routes of administration such as nasal, transdermal or oral. In most cases this has proven to be difficult due to the low stability and membrane permeability of large molecules of biological origin.

More recently, there have been renewed efforts to develop oral large molecule drug formulations.¹⁰ There are considerable technical challenges associated with ensuring sufficient bioavailability from oral formulations of biologics.¹¹

Conclusion
Innovation in formulation development will continue to be driven by efforts to improve drug bioavailability, but other factors such as patient-centricity and advances in processing and manufacturing technology will play an increasingly important part in shaping the industry.

Likewise, the growth of “pharmerging” markets where GDP is lower is likely to further increase the drug industry’s focus on the development of cost effective formulations and technologies. 

References

1. https://www.sciencedirect.com/science/article/pii/S2211383515001069
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334339/
3. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140708
4. https://www.tandfonline.com/doi/abs/10.3109/10837450.2012.660699?journalCode=iphd20
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146086/
6. https://www.sciencedirect.com/science/article/pii S016836590800744X?via%3Dihub
7. https://www.hhs.gov/opioids/about-the-epidemic/
8. https://www.fda.gov/downloads/Drugs/…/Guidances/UCM492172.pdf
9. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/12/WC500199242.pdf
10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908063/
11. http://www.pmlive.com/pharma_intelligence/oral_biologics_delivery_still_elusive_908436

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Torkel Gren is general manager at Recipharm Pharmaceutical Development AB. He holds degrees in Pharmacy and Business Administration as well a PhD in Pharmaceutics (Uppsala University). He has worked in the pharmaceutical industry since 1988 and has held a number of scientist and manager positions in Europe and U.S. He was lead formulator and co-inventor of Detrol OD/Detrusitol SR. Torkel is a member of the board of the Swedish Pharmaceutical Society.