Delivering the Goods

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-04-02-2020, Volume 44, Issue 4
Pages: 28–33

The new molecules entering the development pipeline are bringing forth exciting challenges in drug delivery.

As drug pipelines have expanded to include a wide range of novel, and sometimes difficult-to-handle molecules, so too has the number of methods available to deliver these innovative therapies and drugs. Not only do developers need to consider the route of administration, but it is also necessary to consider solubility, bioavailability, the precise target of the active ingredient, patient convenience and safety, and reducing toxicity, among other factors.

“It is now more common for formulators to be presented with ‘non-druglike’ molecules and yet be tasked with formulating them to achieve high oral bioavailability, good pharmacokinetic properties with minimal toxicity, and good stability,” emphasizes William Wei-Lim Chin, manager, Global Scientific Affairs, Catalent. “The key challenges of these molecules can be attributed to their poor aqueous solubility, poor permeability, or in worst cases both.”

Challenging aspects

These challenging attributes of molecules entering the development pipeline are largely associated with the increasing complexity of molecules, agrees Srini Shanmugam, technical director, Phama Product Development and Manufacturing, Avomeen. “Formulators must balance targeted release profiles for therapeutic efficacy with patient safety and convenience of use,” he says. “Furthermore, every drug delivery system has unique characteristics that come with specific formulation challenges.”

Developing the optimal drug delivery strategy for molecules that are classified as poorly soluble according to the biopharmaceutical classification system (BCS)-that is those molecules in class II and class IV-is a major challenge for industry, notes Archana Akalkotkar, PhD, research scientist II, Charles River. “To come up with alternative approaches that are appropriate for the drugs’ physicochemical properties, as well as the limitations of choice of excipients, which are safe-to-use in the intended species dosed during the preclinical and clinical testing, has been a challenging task,” she states.

For Rich Shook, director, Drug Product Technical Services and Business Integration, Cambrex, there are two main obstacles facing developers in ensuring the optimal level of drug substance is available with a targeted window of transit in the gastrointestinal tract (GI). “One of the main obstacles is the pH dependent solubility and/or degradation of the API, which can decrease the overall absorption of the drug substance and result in a negative impact to the intended therapeutic response,” he says. “The other obstacle is in-vivo delivery of a specific therapeutic dose at a targeted therapeutic site in the GI tract based on the mechanism of action. Some drug substances have a topical mechanism of action on a disease making it important to ensure the release of a high dose of drug substance to that targeted area.”

“In terms of inhalation delivery, the main challenge is the diversity of molecules coming through the pipeline into development,” adds Sandy Munro, vice-president, Pharmaceutical Development, Vectura. “Historically, the inhalation space was dominated by small-molecule therapies for moderate asthma and chronic obstructive pulmonary disease treatments. These days, the interest is much broader both in terms of the diseases that the developers are interested in, and also the range of molecule types.”

Available approaches

There are several approaches available that are in use by developers to help overcome the challenges associated with drug delivery (see Table I for a list of pros and cons for a selection of drug delivery methods and techniques). Approaches such as pH adjustment, co-solvent complexation, solid-dispersion, micellar formulations, among others, help to improve solubility, confirms Akalkotkar. 

“A tremendous amount of knowledge has been accumulated in modern pharmaceutics so that now there are several sets of in-silico guidelines correlating the influence of an API’s physiochemical properties on oral absorption,” adds Chin. “Today, formulators use data to make decisions about their formulation strategy because there is a range of solubilization techniques to choose from. However, sometimes it is easy to get lost in the choice, as data are only as valuable as the insights you can draw from them.”

By way of example, Chin explains that by combining the developability classification system (DCS) along with physiologically-based pharmacokinetics (PBPK) modeling, it is possible to gain insights into a molecule’s developability and the route for selection of the most appropriate solubilization technology. “If a compound is classified as a DCS IIa, it means that the in-vivo absorption of the compound is limited by its dissolution rate, and technologies such as particle size reduction, salt or co-crystal formation approaches can be employed to develop simple formulations that improve dissolution rate,” he says. “For a DCS IIb compound that is limited by its intrinsic solubility, the preferred technology would include lipid formulation or amorphous dispersion via spray drying or hot-melt extrusion.”

For those compounds with permeability issues (classified as DCS III or DCS IV) it is a little more complicated. “As there are several causes of low permeability, a formulator will need to identify a strategy to either stabilize the API from degradation in gastric acid, stimulate lymphatic transport, inhibit P-glycoprotein (P-gp), prevent drug metabolism in the gut, or to alter the permeability of the membrane in the GI tract itself,” Chin continues.


According to Shook, high molecular weight polymer matrices or hydrogels, which use high molecular weight polymers to blend to the drug substance, can create a slow eroding matrix to enable API passage through the GI tract. “These matrices can be combined with enteric components to resist release of the drug substance until it reaches a targeted region of the GI tract,” he says. 

Additionally, Shook notes that enteric coated tablets or multi-particulates can be used to overcome pH dependent solubility issues. “The ratio of types of co-polymers in the coatings can be modulated for a specific pH release profile using in-vitro models to target an in-vivo release of the drug substance in the GI tract,” he confirms. “This ensures that the optimal level of drug substance is presented to the targeted therapeutic region and absorbed.”


An emerging route of oral delivery is in the form of oral thin films (OTFs), adds Shanmugam. “OTFs are polymeric films intended to deliver therapeutic moieties either locally or systemically in the oral cavity or through gastrointestinal absorption,” he notes. “OTFs are an attractive novel drug delivery option and come in two major categories-oromucosal and orodispersible. Oromucosal films are ‘mucoadhesives’, designed to stick to the inside of the oral cavity and release drugs slowly across the mucous membrane, and are fast-acting with high bioavailability. Orodispersible films are non-mucoadhesive and are designed to break down immediately upon contact with saliva.”

This mode of drug delivery is relatively new and so there are limited options currently commercially available, none of which are generic, Shanmugam continues. Yet, the available OTFs do treat a wide range of diseases and disorders and studies have shown that poorly soluble drugs can be incorporated into films (1–4). “However, as this is a streamlined drug delivery system relying on polymers to increase drug solubility, formulators must explore new particle engineering techniques and find innovative ways to solubilize OTFs and incorporate a wide variety of water-insoluble drugs,” he adds.

Within the field of inhalation delivery, there has been some evolution, explains Munro, but the traditional platforms, pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), and nebulizers, are still the mainstay. “Even within these long-established routes of delivery are technology evolutions,” he asserts. “For example, breath activated pMDIs that overcome the issues associated with the coordination of actuation and inhalation, high-dose DPIs that are better able to cope with the demanding new molecules in development, and smart jet nebulizers and smart mesh nebulizers that guide the patient inhalation maneuver to maximize lung delivery.”

Specific considerations

Patient adherence to a therapeutic regimen can be particularly tricky if the route of administration has not been considered appropriately. “When targeting pediatric and geriatric dosing, taste and difficulty in swallowing can hinder patient compliance,” confirms Shook.

Difficulties with swallowing tablets is now thought to affect 37% of the population, states Shanmugam (5). “Children, the elderly, and those experiencing dysphagia or nausea often struggle to swallow tablets and capsules, and, therefore, stand to benefit significantly from drugs delivered without swallowing,” he says. “OTFs have potential in these populations. In fact, the growing size of the elderly population is predicted to drive the growth of the OTF market. Because the elderly population is more prone to chronic illness, the demand for safe and hassle-free drug delivery methods will only increase.”

“A multi-particulate approach can be used in a form of a sachet ‘sprinkle’ formulation with taste-enhancing ingredients,” asserts Shook. “This dose would be added to water or juice which the patient would then drink.” It is also possible to manufacture multi-particulates as a powder for oral suspension (POS) formula, where water is added to the bottles at the pharmacy and given to the patient as a ready-to-dose suspension, he continues. “These methods of drug delivery help address patient compliance while maintaining the target drug substance in-vivo absorption profile,” Shook says.

“In pediatric drug development, many published studies have reported the acceptability and preference of certain dosage forms based on evidence gathered in clinical trials involving children,” adds Chin. Providing examples, Chin highlights that minitablets and syrups have been found to be the most acceptable formulation for toddlers and infants, whereas neonates were found to have increased swallowability of minitablets when compared with syrup (6–9). “For the older children, a preference for chewable and orodispersible preparations were observed when compared with multi-particulates,” he notes.

When considering therapies that are inhaled, the most appropriate method of delivery can depend on the level of coordination, so, for example, younger patients that may struggle with coordination would be more suited to nebulizer therapy or a pMDI used with a spacer, explains Munro. For older children and adults, the delivery method can be more individual and based on patient preference, he continues, but the most appropriate delivery platform may also be driven by the technical requirements of the molecule.

“Smart nebulizer devices come into their own where there is a particular need for efficient lung delivery to maximize the probability of success for a given drug, and where the disease indication can tolerate the higher cost of goods associated with this type of device,” Munro says. “Sometimes this indication is in niche diseases such as idiopathic pulmonary fibrosis (IPF), or in particular sub-categories of a broader disease (e.g., severe uncontrolled asthma) or for a particular development strategy (e.g., fast to clinic development for a biologic).”

Discussing biologics, Chin reveals that the advantages these large, complex molecules can afford over small-molecule therapies include more target-specificity and minimal side-effects, but delivery can be more difficult. “Oral delivery of biologics is far more challenging than it is for small molecules and because of this, biologics have conventionally been delivered in intravenous forms,” he says. “However, there are technologies available to improve the permeability of high-molecular weight biologics and to prevent gastric degradation (e.g., enteric coatings). In addition, spray drying in combination with certain excipients is a promising method for the stabilization of biologics that are usually formulated as liquids.”

For Akalkotkar, targeted drug delivery approaches are more suitable for oncology drugs. “These approaches help reduce the risk of side effects,” she adds. “Continued research is ongoing in this field to develop novel therapeutic modalities. Examples include, magnetic nanoparticles, pH sensitive carriers, and conjugated polymers.”


In great demand

“Novel drug delivery systems offering impactful solutions for the development of new or improved therapeutics are in great demand currently, and are highly sought after by pharmaceutical companies,” says Shanmugam. “In the next 5–10 years, we will see a push toward such systems that address a broad range of clinical and patient objectives, including higher efficacy and bioavailability enhancement, better safety, and improved compliance.”

Therefore, as a result of industry demands, Shanmugam believes that OTFs will grow in importance thanks to the dosing capabilities, packaging, and film stability advantages they offer. “Also,” he continues, “OTFs that are now being developed to enhance solubility can become instrumental in delivering poorly soluble new molecular entities to pediatric and geriatric populations, as well as in extending the lifecycle of such medications that are approaching patent expiration.”

For Shook, the development of nanotechnology will be critical for developers to be able to deliver large and small molecules to a specific site of treatment. “Nanotechnology will ensure that the therapy is introduced and actively initiated at the right time and place to disrupt the disease with precision,” he adds.

The role of connectivity in understanding patient behavior and adherence to medications is important for the future, according to Munro. Additionally, he explains that complex combination products and smart formulations will be vital for the inhalation space.  

“Alongside the traditional small-molecule monotherapy products in development, there are complex combination products, large molecules, and biologics,” Munro concludes. “All of these new molecule types are bringing fresh challenges in terms of formulation and the range of doses that may need to be delivered.”


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5. J.T. Schiele, et al., Eur. J. Clin. Pharmacol., 69 (4) 937–948 (2013).
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Article Details

Pharmaceutical Technology
Vol. 44, No. 4
April 2020
Pages: 28–33


When referring to this article, please cite it as F. Thomas, “Delivering the Goods,” Pharmaceutical Technology 44 (4) 2020.