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Reformulation strategies can provide drug developers with a head start to achieve promising options that benefit the patient.
A recent study has estimated the mean cost of developing a new drug and bringing it to market is $1.3 billion (1). Given this high investment value, the fact that drug development is fraught with potential failure and the increasing complexities of developing difficult-to-handle novel chemical entities, reformulation strategies can provide developers with promising options.
“Due to the high costs of drug development, as well as the high rate of clinical failures, it’s vital that pharmaceutical companies evaluate formulation opportunities for every approved or late-stage clinical product to determine how its commercial lifecycle can be optimized,” explains Paul Spencer, head of Pharmaceutical Polymers and Services, Evonik Health Care. “To minimize regulatory risk and accelerate speed to market, it is common for pharma companies to seek initial approval for products with a simple lead formulation followed by the introduction of superior formulations that can expand the patient population or enhance safety and efficacy.”
“Reformulating an existing drug gives developers a head start, rather than developing a whole new drug from scratch,” says Jeremy Drummond, senior vice-president of Business Development, MedPharm. “This approach cuts product development times because studies can often bridge to those of previous regulatory submissions in particular with regard to non-clinical data.”
“One of the main benefits of reformulating drug products is increasing patient adherence to medicines,” adds Henny Zijlstra, director, Commercial Development, Lonza. Pointing to research from the National Institute for Health and Care Excellence (NICE), Zijlstra reveals that up to half of all patients prescribed medicine for long-term conditions do not take the medicines as intended (2). “Drug developers can help make it easier for patients to take medicines by, for example, changing the tablet or capsule size or geometry to make it easier to swallow or making it so a drug does not need to be taken strictly with or without food,” she says.
Additionally, beyond patient compliance, reformulation strategies have the potential to boost rates of brand preference, notes Spencer. “Reformulation may even help extend the product’s commercial lifecycle through the use of proprietary formulation technologies that can generate outcomes, which are difficult for prospective generic rivals to replicate,” he states.
There are numerous reformulation strategies that are currently employed by the bio/pharma industry, with each offering a different way in which the patient experience can be improved from the original formulation. Examples of reformulation approaches include the following.
Modifying the original release profile. Most reformulation strategies that are pursued by developers of oral and parenteral dosage forms are based upon the modification of the original release profile, notes Spencer. “For oral solid dosage forms, functional excipients can be used to reformulate a product into dosage forms, such as multiparticulates and matrix tablets, to improve product performance,” he says.
Additionally, the drug release profile can be modified by using formulation technologies, which can help improve targetability and oral bioavailability. An example of a strategy to improve bioavailability is through the use of amorphous solid dispersions (ASDs), adds Deanna Mudie, principal scientist, Bend Research, Lonza.
“Enhancing the bioavailability can reduce the dose and remove the food label requirement that calls for patients to strictly take the product with or without food, which can improve patient safety,” explains Mudie. “Food labels may present challenges to patients with trouble swallowing. Additionally, the food label sometimes creates further challenges for patients who have to take medication without food, causing them to skip meals or eat at inconvenient times.”
Other examples of reformulations of oral dosage forms that have been shown to improve patient adherence include minitablets or orally disintegrating tablets (ODTs) that offer improved taste sensation or swallowability for pediatric populations, confirms Spencer.
Changing the route of administration. Administering drug products via an alternative route is another reformulation approach that can overcome limitations of the original form. “For example, converting from oral to inhalation delivery may allow developers to mitigate side effects associated with the drug interacting with the gastrointestinal (GI) tract,” says Mudie.
“For some small molecules and peptides, it is possible to change the route of administration from oral tablets to injectable microparticles and implants,” adds Spencer. “There are a range of successful reformulation examples in this regard, such as a shift from orals to extended release, injectable dosage forms to enhance the treatment of schizophrenia, opioid, and alcohol addition, as well as contraception therapies.”
However, careful consideration is required when reformulating oral dose products as topicals, cautions Drummond. “In this circumstance, the route of delivery is significantly different, and formulation composition can have a major impact on efficacy as well as chemical and physical stability,” he says.
In-vitro models that are based on relevant human tissues to provide results that are directly relatable to clinical outcomes and can also provide answers to specific research questions can help to optimize reformulations, asserts Drummond. “Using these models often leads to novel discoveries that can extend existing patents, making reformulation an attractive option for drug companies,” he states.
Reducing dose frequency. Injectable microparticles that use the biocompatibility and resorption attributes of lactide/glycolide polymers can help to reduce administration frequency or enable localized delivery of drugs, reveals Spencer. “Lactide/glycolide polymers have attained decades of literature in precisely controlling the rate of drug release from microparticles over weeks, months, or a year or more following a single administration,” he says.
“Drug developers may also reformulate drug products as controlled-release versions,” adds Zijlstra. “This method can assist in reducing the dosing frequency, thus reducing the pill burden on patients.”
According to Spencer, ocular drug delivery is currently experiencing intense focus in terms of reformulation. “In ocular drug delivery, it is a therapeutic priority to minimize the number of required intravitreal injections per eye,” he explains. “Here, pharmaceutical companies are developing drugâloaded implants that can safely resorb via hydrolysis after months of drug delivery.”
Combination products. Comprised of two or more components in a single entity, combination products can enable developers to consistently maintain concentrations of API, minimize adverse effects, and reduce the number of dosing units required, confirms Mudie. However, there is the possibility that the single unit may be too large for the patient to swallow, she warns.
Liposomes. “Liposomes have also played a significant role in the successful reformulation of drug products,” says Spencer. “Decades-old cancer drugs reformulated into liposomes and pegylated liposomes are therapeutically efficacious with improved toxicity profiles, better cardiac safety, and less side effects. Antifungal liposomes also show reduced toxicity along with extendedârelease performance, which results in longer retention times of the drug in tissues.”
Additionally, through reformulating pain drugs into long-acting liposome preparations, it is possible to reduce the frequency of epidural injections required, Spencer adds. “In all, several drugs reformulated into liposomes have been strongly preferred to the original dosage forms,” he states.
“When considering drug reformulation strategies, the target patient profile can play a role in developing the most effective product,” asserts Zijlstra. Giving an example, she explains that in the case of geriatric patients, who can have issues swallowing larger tablets, it may be beneficial to reformulate a drug product into a multi-particulate or sprinkle-capsule form, thereby enabling the patient the option to sprinkle the medicine onto food or in water.
“Reformulation strategies can be particularly beneficial to a range of chronic diseases and patient population sub-sets, such as pediatrics or geriatrics,” agrees Spencer. “Improving rates of brand acceptance amongst patient subpopulations, such as pediatrics, are also a key focus of reformulation strategies. Here, the goal of reformulation might be to reduce tablet size, enhance surface coating glossiness, or neutralize bad odors to improve taste and swallowability.”
For Drummond, the needs of the patient must be considered just as much as the chemical and physical properties of the drug in question, irrespective of whether it is a reformulation or a new chemical entity. “These factors all feed into the target product profile,” he adds. “In the case of topical reformulation, transforming an oral product to a topical formulation can often mean moving from systemic delivery to local delivery, which is important to consider when assessing the target patient group.”
In terms of specific disease area, prostate cancer patients have been shown to improve compliance after reformulation of daily injections to a single injection, extended-release, dosage form was done, Spencer continues. “Another example is the reformulation of a drug from a daily oral tablet to an extended-release parenteral dosage form that has improved compliance in schizophrenic and bipolar patients,” he says. “In addition to eliminating the need to remind patients to take their medication, it has also helped addiction patients from intentionally and prematurely stopping their therapy.”
Adding to Spencer’s comments, Zijlstra explains that some relief can be offered to oncology patients if the food label can be removed from the medicine through reformulation. “Many oncology patients have reduced appetites as a side effect of chemotherapy,” she notes. “However, the medicines they are required to take often have food labels on them, meaning that in some cases, the patients must take the dose with food. Therefore, a reformulation strategy that can remove this ‘food’ requirement can improve the patient experience.”
“Furthermore, formulations that combine local delivery with extended-release can dramatically improve rates of brand acceptability for patients who would otherwise face a series of uncomfortable intravitreal injections or injections into the knee or other joints,” Spencer iterates. “Such reformulation options can help to showcase the long-term cost-effectiveness of the drug product and improve reimbursement options.”
According to Mudie, a potential future reformulation strategy could be a digital one. “For example, developers may insert a chip inside a dosage form to alert either the patient, healthcare provider, or both when the medication has successfully been administered,” she says. “This innovation could be useful for oncology patients, who may experience anxiety related to keeping track of their medications. It may also be beneficial for treating schizophrenia, by allowing patients, their families, and their doctors to know with confidence that they have taken their medication on time.”
Moving forward, Spencer anticipates there will be an increasing number of applications for local delivery. “In this application, drug concentrations in local tissues can be maximized for efficacy while minimizing systemic drug exposure resulting in reduced side effects via placement of the drug product directly into target sites, such as joints, the spine, the eye, infected areas, tumors, or the brain,” he notes.
“Furthermore, local delivery can minimize the total amount of dose required,” Spencer continues. “As specialized drugs continue to become more highly potent, the goal of reducing injection volumes and extending the period of drug release will become even more important.” As an example, Spencer highlights a recent approval of an ocular implant, which has the capability of releasing 10 micrograms of drug over a four-month period (3). “Calculated linearly, that’s only 0.00008 milligram of drug per day,” he remarks.
Another approach that may have promise for the future in Mudie’s opinion is the creation of a dosage form that has the ability to release in the GI tract non-traditionally. “For example, it may attach to the intestinal wall and release the drug contents for uptake into the bloodstream,” she says. “This approach could benefit patients who require frequent injections or have harsh GI environments.”
“Finding new molecules that have acceptable therapeutic profiles is not getting any easier,” summarizes Drummond. “Fundamentally, all reformulations, current and future, must benefit the patient, whether by providing a new solution to combating an indication or improving compliance and ease-of-use, to ensure there is no compromise to the patient.”
1. O.J. Wouters, M. McKee, and J. Luyten, JAMA, 323 (9) 844–853 (2020).
2. NICE, “Medicines Adherence: Involving Patients in Decisions About Prescribed Medicines and Supporting Adherence,” nice.org.uk, Clinical Guidance, 28 Jan. 2009.
3. Allergan, “Allergan Receives FDA Approval for Durysta (Bimatoprost Implant) the First and Only Intracameral Biodegradable Sustained-Release Implant to Lower Intraocular Pressure in Open-Angle Glaucoma or Ocular Hypertension Patients,” Press Release, 5 March 2020.
Vol. 44, No. 5
When referring to this article, please cite it as F. Thomas, “A Welcome Change: The Benefits of Reformulation,” Pharmaceutical Technology 44 (5) 2020.