Ronak Savla is scientific affairs manager at Catalent Pharma Solutions.

Ronak Savla

	Every design decision made during drug development has the potential to influence patient outcomes. But how do you convince a medicinal chemist or a formulator that their decision today may impact a patient several years later? What tools and information are available for formulators to routinely design patient-centricity into their work? Are there factors beyond dose, dosing frequency, and dosage unit characteristics (size, shape, or color) that a formulator can influence to improve patient friendliness? How do the best companies share knowledge in the development of patient-focused drug products? 

	With attrition rates that haven’t moved over the past decade and growing pressure from payers and patients, developers are increasingly required to bring drugs to the market that not only have better efficacy and safety but are also designed with patient factors in mind. Scientists involved at any stage of drug development should have a comprehensive understanding of the drug development process and how their design decisions affect downstream development. 

	Despite increased focus on how dosage form impacts patient adherence, safety and efficacy, pediatric patient requirements can still be overlooked or inadequately addressed. The Catalent Applied Drug Delivery Institute sponsored research with the pediatric pharmacy faculty at the Ernest Mario School of Pharmacy at Rutgers University in New Jersey to evaluate the biggest dosage form and administration challenges in pediatric patients, with the aim to bring these insights for pediatric friendly dosage form development (1). 

	Many marketed drugs do not have an age appropriate dosage form, which leads to three times higher drug manipulation (e.g., crushing, splitting tablets, mixing the drug with food or water, and extemporaneous compounding from commercial dosage forms) in inpatient pediatric patients, compared to inpatient adult patients. These challenges are also seen in the outpatient as evidenced by a Catalent survey of caregivers (2), which found that many caregivers had no experience with dosage forms such as softgels, sprinkle capsules, or granules. 

	Challenges in patient acceptance and adherence have seen an increased focus from the industry. These challenges are partly due to the ‘inflated’ physicochemical properties of new molecular entities. The higher LogP and molecular weight lead to poor solubility, low bioavailability, food effects, and patients taking large doses. The implementation of drug delivery technologies has grown to address these molecule challenges, with the aim that it will result in more patient-focused drug products.

	In an analysis of drug approvals since 2009, however, the Catalent Applied Drug Delivery Institute found that 65% of the drugs were not outcome-optimized. The definition of “non-optimized” would be those drugs privy to API-wasting formula, mitigable side effects, low bioavailability, food effect, adherence challenges, complex handling, and increased regimen complexity. 

	Additionally, a survey undertaken by the Institute in November 2018 showed that nearly half the respondents said that they do not have or are notaware of a target product profile (TPP) for the drug they are developing. There is a plethora of literature that investigates drug product characteristics that improve patient acceptance, adherence, and outcomes. 

	As an industry, we are not doing enough to equip formulators, biopharmaceutical scientists, and medicinal chemists with the tools and training to sift through the data and apply key learnings to their daily jobs. In conclusion, an industry-wide adoption and collaboration is necessary to advance how better treatments for patients are designed and developed. 

	The aim of the Catalent Applied Drug Delivery Institute is to bring together scientists and leaders through various mechanisms to generate insights and ideas, share experiences and knowledge, and develop new pathways and tools to apply drug delivery technologies to address unmet patient needs and improve outcomes. 

	1. Catalent Applied Drug Delivery Institute, “Catalent Applied Drug Delivery Institute Partners with Rutgers University to Better Understand the Challenges of Pediatric Drug Formulation and Delivery,” Press Release, July 20, 2017.
	2. D. McDonald, et al., “Medication Administration to Children: The Caregiver Perspective,” EuFPI Conference (London, UK Sept. 12–13, 2018).

Articles

More work needed to advance drug design and development effectively.

Pulling Together to Advance Patient-Focused Drug Products

Small-molecule drugs in oral solid-dosage forms are considered the first line of defense in treating diseases of the gastrointestinal (GI) tract, which affect millions of patients around the world each year. A number of patients, however, either do not respond to these drugs or experience side effects from these drugs. 

	Macromolecular drugs, such as peptides, proteins, and antibodies, offer a newer class of drugs that can treat diseases of the GI tract, such as inflammatory bowel disease (IBD). These drugs have demonstrated improved efficacy and represent a new paradigm of treatments for IBD.

	Macromolecular drugs are usually injected subcutaneously or intravenously, and only a fraction of the administered dose reaches the disease sites in the GI tract. There has been tremendous amount of research to capitalize on the potential benefits of oral delivery macromolecular drugs, which include:

		Better patient acceptance and adherence

		More convenient dosing, including patient self-dosing

	This article reviews current treatment options, analyzes the knowledge and technology gaps that have prevented development of more oral macromolecule dosage forms so far, and discusses some approaches that are being tried and could be used in the future to overcome these gaps.

	Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal (GI) tract that is mediated by the host immune system and is prevalent in Western countries (1, 2). In Europe alone, approximately three million individuals are estimated to have IBD (3). 

	IBD can be subdivided into two types: Crohn’s disease and ulcerative colitis. Inflammation seen in Crohn’s disease spreads deep into tissues and involves the small intestine, large intestine, or both. Patients with Crohn’s disease may have multiple, non-continuous areas of inflammation. Therefore, the drugs must be available at different points in the GI tract. 

	Ulcerative colitis causes inflammation in the innermost lining of the large intestine and rectum. Treating patients with ulcerative colitis requires drugs that are protected and released in the distal portion of the GI track. IBD patients suffer from mild to severe symptoms comprising diarrhea, abdominal pain, malnutrition, and an increased risk of colorectal cancer development. 

	IBD pathogenesis is multi-factorial; therefore, current 

experimental models attempt to address each of the critical elements associated with IBD. Various 

cell-based models are available to mimic the human intestinal mucosa by simplifying the physiological complexity and, thus, allowing the controlled analysis of discrete cell-cell or cell-molecule interactions. Static cultures of intestinal epithelial cells (IECs) are made of one or more cell lines that originate from human colon carcinoma (e.g., enterocyte-like Caco-2 or goblet-like HT29). A more complex 3D co-culture model mimics the intestinal barrier through a co-culture of IECs with immune cells such as macrophages and dendritic cells (4). The addition of pro-inflammatory mediators leads to an inflammatory microphysiological environment with impaired epithelial barrier function and immune cell activation. 

	Another approach to study IBD conditions is the near-physiological 3D model of epithelial organoid cell (EpOC) culture derived from isolated human intestinal stem cells. As an important bridge between the traditional 2D cell cultures and in-vivo animal models, EpOCs could serve as a platform with which to screen various therapies for a personalized medical application.

	Because the gut microbiota of IBD patients is altered regarding composition and metabolic activity, the newer model has been developed to analyze the interaction of potential therapeutics with gut bacteria. The simulator of human intestinal microbial ecosystem (SHIME) is a dynamic in-vitro model used to study of the entire GI tract comprising diverse microbial communities. 

	The pathogenesis and etiology of human IBD have been studied in various animal models that reflect the complexity of the whole organism (5,6). The most widely used animal model, dextran sodium sulfate (DSS) colitis model, is characterized by a loss of epithelial barrier function and the subsequent entry of luminal bacteria into the mucosa.

	Factors that affect drug targeting of the colon can be generalized into pre- and post-absorption challenges (5). Typical pre-absorption challenges include the avoidance of drug absorption and/or degradation in the upper gastrointestinal tract, absorption surface area, mucosa permeability, bile contents, presence of food, and specialized structures such as the Peyer’s patches and lacteal ducts. Post-absorption factors to be considered include potential enzymatic degradation existing in the gut wall and the hepatic first-pass effect. 

	Inter-population differences in gastric functioning and physicochemical characteristics of gastric fluids also impacts drug disposition further down the GI tract (6). Physiological variations such as differences in the transit time, luminal pH, and microbiome in healthy populations versus IBD patients also influence oral drug absorption (

	To date, no cure for IBD exists, and, in severe cases, surgical intervention is inevitable. There is an unmet medical need for novel drugs, and more specific anti-inflammatory approaches, to treat refractory or intolerant IBD patients. 

	Several therapeutic strategies are currently available to reduce the intestinal inflammation, each one targeting a different site in the GI tract (

) (8 –10). Classical treatments for IBD include the use of anti-inflammatory and immunomodulatory drugs such as mesalazine, aminosalicylates, corticosteroids, antibiotics, probiotics, and immunosuppressants such as cyclosporines (8, 9, 11).
	

	Biological therapies have also been developed to target specific IBD pathways. Monoclonal antibodies may be used, for example, to block, selectively, such pro-inflammatory cytokines as tumor necrosis factor- (TNF). In addition, anti-cell-adhesion antibodies such as integrin blockers may be used to help inhibit lymphocyte migration to the gut. However, these biological agents are not effective for all patients with IBD and may increase the risk of infection and the potential for immunogenicity. 

	A newer strategy focuses on inhibiting signaling by using small molecules to transport Janus kinase (Jak) inhibitors, which can block numerous key cytokines associated with IBD, simultaneously. Unfortunately, these new treatments pose safety questions. Clinical trials are currently exploring more selective targeting of single Jak inhibitors, for example, using RNA interference (RNAi) via synthetic siRNA, to downregulate Jak expression in a specific manner. Advanced drug-delivery strategies are indispensable to successfully deliver siRNA to the target tissue or cells.

	So far, FDA has approved two anti TNF antibodies, Infliximab and adalimumab, to treat moderate-to-severe active Crohn’s disease or ulcerative colitis. Because they are biologics, both drugs are administered by injection. Infliximab requires intravenous infusion on weeks zero, two, and six, and then every eight weeks. Adalimumab is administered as a subcutaneous injection on Days 1, 15, and 29, then every other week. Both treatments pose the risk of adverse effects (12). Ustekinumab is another monoclonal antibody indicated for the treatment of moderate to severe Crohn’s disease, which targets IL-12 and IL-23 cytokines. The initial dose is administered as an intravenous infusion and is followed by maintenance therapy of a subcutaneous injection every eight weeks. 

	Being able to deliver macromolecular IBD treatments orally would improve patient experience, avoid systemic exposure, and increase drug presence at disease sites. However, maintaining stability and activity in the GI is a significant challenge. So far, in studies that have evaluated the potential for oral delivery (13 – 16), considerable variability has been seen in the recovery, stability, and activity of orally administered macromolecules.

	Clinical trials of target oral therapies for IBD have also shown insufficient results. One case in point is Mongersen (GED0301), a 21-base single-strand antisense oligonucleotide that complexes to Smad7 mRNA to cause degradation via the classical antisense pathway (17) to restore the function of TGF-1’s anti-inflammatory actions. The compound was tested in modified-release film-coated tablets using methacrylic acid-ethyl acrylate copolymers as a pH-dependent coating. The target treatment areas were the lumen of the terminal ileum and right colon. However, results were inconclusive, and clinical trials were discontinued in October 2017. 

	Another compound undergoing clinical trials is AVX-470, a novel polyclonal anti-TNF antibody candidate isolated from bovine colostrum, whose in-vitro activity is similar to that of infliximab (13). Disease severity was reduced when the murine version (AVX-470m) was orally administered in mouse models of IBD. Minimal systemic exposure was seen in mouse models. 

	A Phase I placebo-controlled study in 36 ulcerative colitis patients assessed the safety, pharmacokinetics, immunogenicity, and efficacy of four weeks of treatment (18). Clinical response was seen in 25.9% of patients and only treated with the candidate therapy, compared to 11.1% of the patients who received the placebo.

Formulation and dosage-form considerations

	In addition to addressing stability, to ensure that the drug remains in the GI tract long enough to be effective, targeted delivery to the colon is the greatest challenge for developing oral therapies for IBD. Most current approaches use an enteric coating system to protect the drug and only release it at target sites. However, each IBD patient has a different disease profile, so a formulation that, for example, releases in the colon will not help a patient whose IBD affects the small intestine.

	Ensuring sufficient residence time in the GI tract will require use of a toolbox of technologies and approaches that are designed to enhance the predictability and reproducibility of targeting of the drug in the colon. 

	Use of pH-sensitive polymers. Once the macromolecule is exposed to the environments of the small and large intestines, proper formulation and dosage form design can help ensure that it retains activity. One formidable challenge is to protect the macromolecule from the acids that are secreted by the stomach until the dosage unit reaches IBD sites in the intestines. 

	Use of a coating system can help control the release the macromolecule at specific pH points. One of the approved therapies for IBD, the small molecule, mesalazine, use different grades of Eudragit polymers to achieve specific release profiles. Even though this example is a small molecule, the principle of using coatings for controlled release could also, in theory, work for larger molecules, as was shown in clinical trials (e.g., for mongersen).

. Biodegradable polymers, known for their low toxicity and biodegradability, have been extensively used to formulate GI tract treatments that target the lower GI tract. Within the colonic environment, these mostly hydrophilic polymers can be broken down by various bacteria (19) for a controlled release of the drug within the colon. These polymers can be combined or used individually to modulate the rate of drug release and absorption (19). Options include guar gum, pectin, chitosan, chondroitin sulfate, galactomannan, and amylose, all of which are categorized as “generally regarded as safe” (GRAS).

. Mucoadhesive systems have been designed to increase the time that the formulation is retained within the GI wall in order to increase absorption of poorly absorbable drugs or improve their topical application (20). Some of the better-known mucoadhesive polymers include polycarbophils, polyurethanes, and polyethylene oxide. 

. Although most efforts to develop oral dosage forms for GI therapies focus on capsules or tablets, this approach may not allow the drug to be adequately released at all disease sites throughout the small and large intestines. 

	Using multiparticulates, formulating dosage units with different coating systems may be more efficient. The size of the pylorus is known to be around 7–8 mm when a patient is fasting, decreasing to 2–3 mm after a patient has eaten. Multiparticulate dosage units smaller than 2–3 mm in diameter would be able to leave the stomach, whether the patient was in a fasting or fed state.

. Micro- and nano-particles represent novel approaches to localized delivery. Taking advantage of the GI tract’s leaky epithelial barrier, these particles tend to accumulate in inflamed portions of the GI tract, optimizing drug delivery. In murine models and first-in-human clinical trials, nanoscale particles were found to accumulate in inflamed areas (21).

	Smart delivery of nano-scale systems takes advantage of the physiological homing mechanisms to the site of injury and inflammation (

), and nanotechnology is an area of intense research and development for GI-tract therapies that target the colon (22).
	

	Other options for controlled and targeted release include prodrugs, embedding the drug in a matrix, and using osmotic control for delivery. Ultimately, the choice of delivery system depends on many factors, including target product profile. 

lists the pros and cons of a number of available technologies.
	

	Small-molecule drugs have been the treatment of choice for IBD, but a large percent of patient eventually don’t respond the therapy. Macromolecular drugs are a newer class of drugs that have improved efficacy and require injection. Researchers are studying oral delivery approaches for macromolecular drugs that have better patient acceptance and adherence, more convenient dosing, and an improved therapeutic profile. Before patients can benefit, researchers must address the technology gaps that have prevented development of more oral macromolecule dosage forms.

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	Vol. 42, No. 7
	July 2018
	Page: 32Â­–40

	When referring to this article, please cite it as R. Savla, O. Hartwig, W. W. L. Chin, B. Loretz, and C.M. Lehr, “Oral Delivery of Macromolecular Drugs" 

* is scientific affairs manager at Catalent Pharma Solutions, Somerset, NJ, 

is a PhD student at the Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany; 

is a technical specialist, science and technology, at Catalent Pharma Solutions, Eberbach, Germany; 

is head of the drug delivery department at HIPS.

To whom all correspondence should be addressed.

Macromolecular drugs are typically injected, but oral dosage forms are being developed to improve the treatment of gastrointestinal conditions such as inflammatory bowel disease.

Oral Delivery of Macromolecular Drugs

Each year, the amount of money spent on oral drug development increases, but the number of drug approvals remains relatively constant (1). Even for drugs that are approved, the industry-wide return on R&D investment has declined for the past decade and reached the nadir in 2009-2011 (2). An increasing percentage of new chemical entities (NCEs) are progressed through development by smaller companies, so the pipeline is spread across a more diverse industry.

	Nearly one-third of drug candidates fail in preclinical studies with nonclinical toxicology accounting for half of the failures (3). Recent analyses showed that 60-70% of drugs in Phase I progress on to Phase II, and the progression rate is slowly declining since 1997 (4, 5). Reliance on conventional formulation strategies to solve suboptimal pharmacokinetics of Developability Classification System (DCS) Class IIb lead compounds has been shown to increase timelines by approximately two years (6). 

	Well-funded and well-run smaller companies can provide several benefits to patients: they work on disease states that are of less interest to big pharmaceutical companies (e.g., cystic fibrosis and rare cancers), they lack bureaucracy and red tape, and by outsourcing some or all their needs, they don’t need to maintain and utilize a large footprint of pharmaceutical development and manufacturing capability. There may be some significant challenges also. With a smaller employee base, there is a smaller pool of brain power available to resolve significant challenges. Smaller teams can act fast but might miss details that would be captured in a larger team or organization. A contract services organization can add capabilities, resources, and knowledge to help prevent mistakes that can delay or prevent advancement of a drug at any stage of development. 

	This article focuses on one problem area: the transition between molecule development and dosage form selection. 

	Molecule development and dosage form selection

	In small companies, these two phases in product development, though part of a continuum, are hampered by an ideological separation between medicinal chemistry and dosage form selection (see 

), and the transition between them is not as smooth and efficient as it could be. Typically, the medicinal chemist who is responsible for molecule development is not the same person as the formulation scientist who is responsible for dosage form selection. If the molecule was acquired from another company, or if the formulation selection is outsourced, this is almost certainly the case. This practice is understandable, because the kind of work that is done is very different and it is more efficient to separate the functions. The molecule development function screens a sometimes large number of molecules or molecule fragments to select those that have the most promising target specificity and 

 potency leads to inflation of molecular properties (7), often at the expense of biopharmaceutical properties. Coupled with a misinterpretation of Lipinski’s Rule of Five (Ro5), a rule of thumb to determine if a chemical compound meets certain chemical property requirements that would make it a likely orally active drug in humans, it is not rare for chemists to develop molecules with LogP in the range of 4.5 to 5 and molecular weight approaching 500 Daltons, both of which do not violate Ro5. 

	One major issue for drug delivery is that water solubility is typically too low and leads to progression of unoptimized drugs (7) or increased timelines (6). Another issue is that a specific molecule may exist in multiple polymorphic forms with different properties that could have a major influence on solubility and manufacturability. One study found that 89% of molecules had more than one polymorphic form (8). The molecule can be modified to produce a salt or a co-crystal to further modify its solubility, purity, or manufacturability. The real problem is that when a medicinal chemist is balancing the structure, activity, and property requirements of candidate molecules, they are not typically thinking about how the drug will be dosed to patients, and whether their choices are in alignment with the formulation and dosage-form technologies that may be needed.

	Exactly when a company engages formulation scientists during molecule development varies between companies. In the authors’ experience, frequently formulation scientists join the process too late, after salt form and polymorphic form have been decided. Because most compounds are poorly water soluble, the formulator has a significant problem if solubility of the salt form is still not high enough or if the solubility increase must be countered by an increase in molecular weight.

	This disconnect can be seen in the approach that most small companies follow in trying to resolve the solubility issue: addressing one function after the other, rather than together concurrently. A 2007 study found that early in the development process, salts are selected based on ease of synthesis and crystallization, cost of raw material, etc (9). Unfortunately, focus on downstream processes (physical and chemical stability, processability into dosage forms, solubility, and dissolution rate at different pH conditions) is often absent. It is difficult to change the salt form in later stages of development without significantly increasing timelines and costs and requires a company to repeat biological, toxicological, formulation, and stability tests. 

	When the medicinal chemist chooses a salt form to improve solubility, they add to the molecular weight of the molecule. While hydrochloride salts are relatively small (MWt 36.5 g/mol), there are data to show that solubility improvement may be limited by the counter-ion effect (10); as a result, molecular chemists are turning to different salts. Some of the more commonly used salts are relatively large-such as tosylate with MWt 172 g/mol-which would increase the molecular weight by 22-43% for a molecule with molecular weight in the range 400-800. This extra molecule “baggage” needs to be carried by whatever drug delivery system is chosen. In a powder-filled capsule, this can be tolerable but in any other formulation with a drug loading of less than 100%, the excipient loading becomes a multiple of the molecular weight increase provided by the salt and the drug loading (see 

). This means a larger pill, and potentially more pills, for the patient to swallow.

	The formulator needs to balance target dose and target bioavailability against pill burden to deliver an efficacious medicine that a patient will want to take as long as needed. When employing technologies for solubility enhancement, the type and quantity of excipients used are crucial to performance, and thus high drug loadings may be difficult to achieve without sacrificing performance. If the formulation is more effective at improving solubility than the salt form, then it makes more sense-all other things being equal-to use the original molecule in the drug delivery system rather than the salt.

	The DCS proposed by Butler and Dressman (11) is useful to help guide technology selection, but is not widely used. In this classification, drugs are partitioned into four classes based on their jejunal permeability and the volume of simulated intestinal fluid needed to dissolve an entire single dose (see 

	DCS also calculates the solubility limited absorbable dose (SLAD), above which no more drug is expected to dissolve during the transit time through the small intestine, and this is used to split DCS Class II into molecules with dissolution rate limitations (DCS Class IIa) and solubility limitations (DCS Class IIb) to oral absorption. When reviewing DCS, it is important to remember that dose means the maximum dose taken by a patient at one time (not the highest strength dosage unit), and this number is increased during ascending dose studies.

	A classification of GlaxoSmithKline candidates-and likely to be representative of the industry at large-found that 65% of NCEs could be classified as DCS IIa/IIb (dissolution rate or solubility limited) (3). It is possible for a well-soluble DCS Class I molecule to be DCS IIb at the maximum tolerated dose. Whenever a compound is classified as DCS IIb, employing particle size reduction alone or dosing as a solution (e.g., in polyethylene glycol) would not be expected to increase solubility, and solubility-enhancing technologies such as amorphous dispersion, lipid formulation, or perhaps co-micronization should be considered instead, as these technologies are likely to have a far greater impact on the SLAD (see 

	Unfortunately, there is still a relatively higher percentage of molecules progressing to Phase I with simply a dissolution rate enhancement and/or powder in capsule approach. This results in compounds that have poor exposure, do not reach maximum tolerated dose levels, and are likely to show lack of efficacy in late-stage clinical trials.

	It is recommended that formulators are involved in the later stages of candidate screening, during the selection of salt form. By proper application of science, it should be possible to build a bridge between the two disciplines (

), anticipate the DCS classification and dose, and therefore determine which technologies will be required for human clinical trials, including assessment of both salt form and dosage form-all at the same time, which could save weeks if not months of time. 

. 1, 191-200 (2012).
	2. K. Smietana, et al., 

. 14, 455-6 (2015).
	3. M.K., Bayliss et al., 

, 21, 1719-27 (2016).
	4. K. Smietana, M. Siatkowski, M. Moller, 

, 32, 40-51 (2014).
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, 7,1007-26 (2007).
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Salt Screening and Selection: New Challenges and Considerations in the Modern Pharmaceutical Research and Development Paradigm. Developing Solid Oral Dosage Forms-Pharmaceutical Theory and Practice

, 1st edition (Elsevier, Inc, USA, 2009).
	11. J.M. Butler and J.B. Dressman, 

Vol. 42, No. 4
	April 2018
	Pages: 72–77

	When referring to this article, please cite it as S. Tindal and R. Savla, “Bridging the Gap from Molecule to Drug,” 

Formulation expertise can smooth the transition of a prospective therapy from medicinal chemistry to drug dosage form.