Considering Bio/Pharma Reformulation Strategies

De novo drug development is well known to be inherently costly and associated with a significant risk of failure. It has been reported that, on average, companies can spend $2.7 billion in bringing a drug through the full product lifecycle (from invention to commercial launch) in a process that can last between 10 and 15 years with a 90% rate of failure (1).

As a result of the significant cost of development, companies seek to recoup finances through data exclusivity and patent protection of intellectual property, such as the drug product’s formulation. When the drug is nearing the end of its patent or no longer has market exclusivity, reformulation strategies can be a useful tool to stretch out a potential asset lifecycle.

However, reformulation strategies are not just a means of elongating market presence for drug products or maximizing the potential return on investment. Bio/pharma companies reformulate existing therapies for a whole host of reasons, such as treating underserved or neglected disease areas, improving patient adherence (particularly for target patient groups, such as pediatrics), reducing the potential of drug abuse, and providing alternative options in crisis situations—as has been apparent during the COVID-19 pandemic.

Treating new indications

Many existing therapies have undergone reformulation to provide treatment options for other disease areas. For example, minoxidil, which was originally formulated as a tablet to treat hypertension, has been reformulated for topical use to treat male pattern baldness (2). Additionally, drugs have been repurposed for new indications when they have failed clinical trials or were withdrawn for safety reasons. For example, sildenafil was originally formulated for the treatment of angina; however, the therapy did not successfully complete clinical trials for this purpose. Pfizer then invested in research around an observed erectogenic side effect, and it has since been reformulated for the treatment of pulmonary arterial hypertension (2).

Recently, researchers have been evaluating the potential of formulations of pentamidine with Pluronic (BASF) micelles, which act as drug solubilizers or controlled drug-release agents, to treat Human African trypanosomiasis (HAT or sleeping sickness)—a neglected tropical disease (3). Pentamidine is an anti-infective agent that can be used to treat an earlier stage of the disease; however, it is unable to penetrate the blood-brain barrier sufficiently to treat the secondary stage of HAT. Therefore, it was hypothesized that a combined pentamidine-Pluronic formulation may be a suitable approach to provide patients with a single therapeutic option for treatment of all stages of HAT. Although, due to time and money constraints, the researchers were unable to significantly enhance brain exposure of the active ingredient using a formulation incorporating Pluronics, they did produce a significant body of high-quality data for use by other researchers in the future (3).

In other research, a new formulation of risperidone is being investigated, repurposing the therapy from an antipsychotic to an adenocarcinoma treatment (4). Previous work has been inconclusive on the anti-cancer benefits of risperidone, although it has been used off-label in the palliative care of late-stage cancer patients. In the study, the researchers explored the formulation of risperidone with a naturally-occurring conjugated linoleic acid (rumenic acid) and lipid excipients—VAL401.

When compared with conventional risperidone therapy, the researchers found that the reformulated drug in a lipid excipient resulted in a similar rate of exposure to the active moiety. As a result, it was concluded that the pharmacokinetic data attained supports the use of safety and tolerability data from the conventional risperidone formulation for further testing of VAL401 (4). Based on these results, it is hoped that the drug will be able to proceed into later stage clinical trials with the original drug’s established profile being used to appease regulatory requirements.

Improving patient adherence

Patient adherence or non-adherence to a therapeutic regimen can mean the difference between success or failure in terms of treatment. Adherence to a medication regimen can be particularly poor for elderly patients, pediatric patients, and patients dealing with chronic, long-term diseases and disorders.

Alterations to the route of administration can be a useful tactic to help improve patient adherence. Moving away from intravenous injections to subcutaneous ones, for example, can lower both the burden on the patient and healthcare providers, as care can be provided in a home setting. Or, utilizing a delivery technology, such as orally disintegrating tablets (ODTs), could facilitate administration of oral dosage forms to pediatrics and patients who struggle to swallow tablets.

For the latter example, a recent deal between Catalent and Edenbridge Pharmaceuticals was agreed upon for the formulation of glycopyrrolate as an ODT form (5). Glycopyrrolate is an anticholinergic drug that has been commonly used control peptic ulcers and to reduce severe or chronic drooling in pediatric patients with neurologic conditions (6). With the agreement between Catalent and Edenbridge, it is hoped that the proven drug can be reformulated into a novel drug platform to provide benefits to patient populations where fluid intake may be limited (5).

Another important aspect of improving patient adherence is that of preventing abuse of therapeutic products—an issue that has been at the forefront of efforts by pharma companies to tackle the opioid crisis. There are several reformulated products currently available that feature abuse-deterrent properties. To create an abuse-deterrent formulation, products can contain excipients that will form a gel if the product is tampered with, they can be formulated to be resistant to crushing or physical manipulation, or the formulation can include a sequestered antagonist (7). However, these abuse-deterrent formulations are limited in application as a result of the cost associated with them.

Impact of COVID-19

There have certainly been lots of instances of repurposing and reformulating drugs for the potential treatment of COVID-19. And, as was discussed in a recent article (8), vaccine developers are looking toward the inhaled route of administration to help ensure the needs of pediatric patients and those who fear needles can also be met in the fight to combat the virus.

Some other research in the area of pandemic response, however, has focused on nano-techniques. For example, recent work from researchers at the University of Liverpool’s Centre of Excellence for Long-acting Therapeutics (CELT) has assessed the potential of a nanoparticle formulation of niclosamide (NCL)—a cheap API that has been shown to be highly effective against SARS-CoV-2—to treat COVID-19 (9).

In the study, the CELT scientists used nanoprecipitation to form redispersible solid drug nanoparticle formulations of NCL, which means that the API did not require nanocarrier encapsulation and, as a result, did not suffer from limited drug loadings (9). The formulated NCL can be stored as a solid and then reconstituted with water to be used as a long-acting injectable. The study results showed that there was a sustained level of NCL in the plasma concentrations of rats for a 28-day period post-injection, which was administered once, intramuscularly (9).

“Repurposing of medicines for SARS-CoV-2 has yielded mixed results, with some clear successes for immunomodulatory drugs such as dexamethasone, and work underway to repurpose drugs like favipiravir and molnupiravir that were designed for other viruses,” said Professor Andrew Owen, a pharmacologist and co-director of CELT, in a press release about the study (10). “The ultimate utility of our long-acting injectable can only be determined in adequately powered and well controlled randomized clinical trials, but unlike other drugs that have been explored for repurposing niclosamide, target concentrations may be achievable in humans. The formulation has shown great promise in preclinical studies at a time when it is increasingly evident that drugs are urgently required to complement the vaccines.”

“Repurposing drug compounds is much more than using existing medicines for a new disease,” added Professor Steve Rannard, a materials chemist and co-director of CELT, in the press release (10). “The existing active drug compound needs to be shown to be active at a significant level, then reformulated to address new challenges. The conventional route of administration may also not be relevant, and modifying the way the patient receives the drug compound is highly critical to efficacy.”

References

1. K.C. Venneti, et al., J. Biol. Today’s World, 9 (3) 216 (2020).
2. S. Muerteira, et al., J. Mark Access Health Policy, 1, 21131 (2013).
3. L. Sanderson, et al., PLoS Negl. Trop. Dis., 15 (4) e0009276 (2021).
4. S.J. Dilly, et al., Eur. J. Drug Metab. Pharmacokinet., 44, 557–565 (2019).
5. Catalent, “Catalent to Supply Edenbridge Pharmaceuticals with a Patient-Focused Fast-Dissolved Zydis Formulation of Glycopyrrolate Intended for Use as Adjunctive Therapy in the Treatment of Patients with Peptic Ulcer,” Press Release, Aug. 10, 2021.
6. C. Multum, “Glycopyrrolate,” Drugs.com, April 10, 2020.
7. F. Thomas, Pharm. Tech., 44 (6) 24–27 (2020).
8. F. Thomas, Pharm. Tech., 45 (9) 26–28 (2021).
9. J.J. Hobson, et al., Nanoscale, 13, 6410–6416 (2021).
10. University of Liverpool, “Long-Acting Injectable Medicine as Potential Route to COVID-19 Therapy,” Press Release, April 14, 2021.

About the Author

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Article Details

Pharmaceutical Technology
Vol. 45, No. 10
September 2021
Pages: 30–32

Citation

When referring to this article, please cite it as F. Thomas, “Considering Bio/Pharma Reformulation Strategies,” Pharmaceutical Technology 45 (10) 2021.