Describe recent advances in oral routes of drug administration.
RL: Over the recent years the share of BCS class II (low solubility, high permeability) drug candidates in the pipelines of innovator companies has grown to about 70% of the overall candidate portfolio. For many of these candidates their low solubility in the GI tract directly translates into poor bioavailability. Hence, one of the most important areas for oral drug delivery has been overcoming the solubility-driven bioavailability challenges of these compounds. Specific technologies developed to address this issue have helped to enable several important novel medicines and also to improve upon existing ones via lifecycle management efforts. Among the technologies developed to date, four stand out due to the fact that applying them, highly relevant medicines have been introduced into the market and are available to the patient today. These four technologies are: self-emulsifying drug delivery systems, nanocrystal formulations, solid dispersions made by hot melt extrusion, and spray dried solid dispersions.
HC: Recent advances in oral route of drug administration include better understanding of drug absorption process and significant development in various drug delivery systems. Successful development of poorly soluble drugs through oral route had helped in changing the mindset of pharmaceutical companies and emphasis on extensive characterization of physicochemical properties at early development stages has significantly improved the chances of their successful delivery.
AG: The advance I am most interested in is conceptual—namely the slight shift in attitude by the regulatory authorities to the development of solid dose forms for the pediatric population. While this in itself is not a technology innovation, it is a trend that offers opportunities to drug delivery and innovative excipient companies in this area. The regulatory bodies have essentially opened the door to tablets for children much younger than had been previously recommended. This opens the way for mini-tab and orally dispersing powders/granules to be utilized more effectively.
Essentially, during AAPS 2012, the chair of the EMA Paediatric Formulation Innovation Committee and the FDA director of the Division of Product Quality Research made several comments on the subject of dosage forms and excipients. The one I am most impressed by is “Placebo tablets have been shown to be accepted by two to three year olds, who even preferred it to syrup,” she said. “The parents preferred it too because often the work involved preparing medications – such as mixing it with food products – is tricky and easy to get wrong.”
This is a tacit statement accepting that oral solid dose forms MUST be considered even for very young populations, in light of the regulations around new product development for pediatrics.
SC: SPI Pharma has been working on improving the efficacy of orally administered drugs by enabling faster onset (Tmax) and a reduction of dosage to lessen side effects without compromising the effectiveness (AUC) through excipient platforms and formulation techniques. We have developed some expertise in this area, working with insomnia and antipsychotic API’s. The final formulation that was targeted to be administered orally showed, in a full clinical study (NDA), shorter Tmax compared to the innovator product and similar AUC as the innovator at reduced drug loading. This was accomplished in this application through a combination of innovative dosage form and improved permeability through formulation modifications.
SA: Oral drug delivery remains the most common route of administration of a large number of drugs primarily due to the availability of a variety of formulation technologies. The oral dosages such as tablets (swallowable, chewable and suckable) and suspensions and capsules (hard and soft gels) are widely viewed as patient compliant. In certain groups of patients, especially within pediatric and geriatric groups, orally disintegrating tablet (ODT) formulation remains the most preferred route of administration. To meet the unmet challenges, the industry is developing the brand and generic drugs for immediate and controlled release for life cycle management. But, the challenges in developing an oral tablet are multi-fold which could stem from taste masking, poor flowability and compressibility, and poor solubility. The latter has become a subject of continued focus in the industry because a large percentage of new chemical entities (NCEs) are poorly soluble and bioavailable. The excipients’ manufacturers are bringing in new and innovative polymers and solubilizers to find the desired solutions.
Discuss how our understanding of drug absorption has evolved and grown increasingly beneficial to the industry.
RL: Over the past 20 years, our understanding of oral drug absorption has benefitted from a significant body of research conducted in this important area. Today, we are able to better model, predict, and test drug absorption than ever before. Significant milestones in this area have been the introduction of the Caco-2 cell line for permeability testing, the creation of the Biopharmaceutics Classification System, and the development of a series of in vitro and in silico tools to test various factors which are relevant for drug absorption. This important domain of method development is still very intriguing with many research groups devoting significant efforts towards optimizing the toolbox for researchers and formulators alike. Furthermore, and bridging from applied drug delivery to compound finding and optimization, the field of developability of new candidates for optimized oral delivery has made huge progress over the last decade. Today, this very progress allows the design of novel compounds with suitable physico-chemical and biopharmaceutical properties in addition to the desired pharmacological activity.
HC: Recent research on mechanisms involved in drug disintegration, dissolution and permeability has increased the understanding of absorption process. Further, utilization of various modified dissolution apparatus and in vitro and in vivo correlation has been beneficial to the pharmaceutical industry. Use of modeling in designing experiments and evaluating gastrointestinal parameters through software like GastroPlus™, etc., had helped in optimizing factors/variables to achieve high bioavailability.
AG: I flip now to the other end of the age scale here to discuss our understanding of drug absorption. In particular I want to highlight the need for more appropriate dosage forms that take into account the changing drug absorption and metabolism as the population ages. In recent years our awareness of the rapidly expanding geriatric or ‘aging’ population has demonstrated we must know more about this patient group. It is well recorded that as we age a number of physiological changes can occur. It is common for total body fat to increase while total body water decreases, and the change in this fat-to-water ratio can affect the distribution of hydrophilic and lipophilic APIs. Other common changes include higher gastric pH, less hepatic mass and blood flow, reduced kidney function, altered plasma protein binding, and reduced drug metabolism. These changes can lead to serious adverse drug reactions.
We must look to including a greater number of the aging population in clinical trials if we are to truly gain benefit from understanding drug absorption. This population group will become an ever more costly burden on global healthcare systems if the current rates of non-compliance or adverse reactions continue.
One study I recently reviewed highlighted that of patients exposed to polypharmacy, 35% experienced adverse drug reactions. Many were predictable and too many led to hospitalization.
SC: A key to effective therapy is “drug absorption”, which has been extensively researched and developed. An effective absorption of the active drug molecule into the blood stream can result in reduction of API dose per tablet, thus reducing the risk of side reactions. Some of the well-known drugs have shown bioavailability of less than 50% in the GI due to “first pass” and “food effect”. SPI has had the opportunity to address this through solubility enhancement of API’s as well as through formulation modifications.
SA: The absorption in the gastrointestinal tract (GIT) is critical for therapeutic efficacy of a drug. The lack of adequate solubility and permeability of the drugs (BCS Class II and Class IV, and Class III) remains a challenge since over 70% of drugs are poorly soluble and/or also less permeable, hence, their absorption is limited. Furthermore, the safety concerns associated with higher dosing limited by poor absorption have heightened awareness. As a result, the recent efforts are focused on designing smaller and smarter pills with reduced side effect profiles. A number of analytical tools have been used to assess the APIs’ physico-chemical properties, pharmacokinetics and pharmacodynamics, and assess the in vitro in vivo correlation (IVIVC) to further improve the understanding of safety and efficacy of drug substance and drug products.
What are the most effective strategies for enhancing oral bioavailability?
RL: There are various strategies for enhancing poor oral bioavailability of developmental and marketed drugs. Which one will be most effective largely depends on the root cause for the observed low bioavailability of the drug substance at hand. One needs to analyze all aspects which may contribute to poor oral bioavailability in the first place, understanding the solubility and stability of the drug in physiologic media at relevant dose concentrations, its permeability of biologic membranes, and its proneness to pre-systemic and/or hepatic first pass metabolism. In case the low bioavailability is driven by poor solubility, choosing from the approaches discussed under the first question, including solid dispersions, will be a reasonable strategy. To overcome low bioavailability driven by pre-systemic degradation due to exposure to low pH values in the stomach, enteric coating of multi-particulate systems is a proven strategy. If, on the other hand, poor permeability of biological membranes (BCS class III compounds) or extensive presystemic metabolism drive low bioavailability, medicinal chemistry-based approaches including prodrug strategies might offer the solution.
HC: Selecting the right technology for enhancing oral bioavailability based on the understanding of the physicochemical properties of the drug is the most effective strategy. Properties like Molecular weight, Log P, permeability, pH solubility and stability profiles, etc., should be extensively evaluated. Selection of appropriate delivery techniques based on practical considerations and in-house expertise should be a part of strategy.
SC: There are several strategies discussed in literature, like nanosizing, solid dispersions, pegylation, and pH modifications to name a few. However, these techniques can be expensive and may result in reduced performance of the drug. SPI Pharma has developed a specific excipient for enhancing the oral bioavailability without the need to alter the drug substance. We have been successful in the development of an insomnia drug for one of our customers, which successfully went through full clinical trials and got approved. We are now exploring the use of this excipient in other model drugs.
SA: The strategies for enhancing the oral bioavailability of drugs are (i) solid dispersions (ii) self-emulsifying drug delivery systems (SEDDS/SMEDDS) technologies. Both technologies are widely used in the industry today. The solid dispersions technology is, however, highly preferred over liquid or soft gel due to the availability of a range of polymers, and many of the products have been marketed in amorphous dispersions. The hot melt extrusion (HME), in particular, is most widely used for converting the high melting and crystalline APIs to amorphous solid dispersions (ASD), and enhancing the oral bioavailability. As solvent free, the melt extrusion process has accelerated drug development in saving time and cost as compared to spray drying due to an amenable downstream process. That led to a paradigm shift and more drug manufacturers are using melt extrusion in the development of NCEs and also generic drugs. Other newer technologies, such as Kinetisol®, a solvent free and high shear mixing process, and electrospraying/electrospinning are also gaining grounds steadily to address the unmet solubility challenges.
In spite of a greater interest in amorphous solid dispersions, the nanoparticulates and self-emulsifying delivery systems have been used more frequently due to the availability of a range of safe solubilizers, co-solvents, surfactants, and polymers. A number of CROs and CMOs are equipped and well positioned to expedite the drug development from R&D to manufacturing in order to save time and cost.
Discuss approaches to combating poor aqueous solubility.
RL: The best approach to overcome poor aqueous solubility of a given drug is to disrupt or dissolve its crystal lattice already before the patient ingests the final drug product. Applying this strategy can be done in various ways, and 4 important ones have been mentioned already. During the production of self-emulsifying drug delivery systems typically a solution of the drug in lipophilic excipients is prepared. Media milling with polymeric excipients on the other hand disrupts the crystal lattice and leads to nanocrystal formulations. Solid dispersions can be obtained via application of heat (hot melt extrusion) or organic solvents (spray drying). All technologies have in common, that they lead from the drug substance to an intermediate which, upon further processing, is converted into what looks and can be used by the patient like a conventional dosage form: a tablet or a capsule. Which of the 4 strategies is the best for the given delivery challenge needs to be evaluated via the appropriate formulation design work.
HC: Solid dispersions, nanotechnologies like polymeric and solid lipid nanoparticles, self-emulsifying drug delivery systems are key approaches to combat aqueous solubility.
AG: The obvious approaches have been to reduce particle size, thereby giving the product greater surface area, but any good chemist will tell you this does not improve the real solubility. Alternatives are to move to an enhanced physical transformation with nano-sizing and then reduce its crystal structure to that of an amorphous compound. In the latter case this can and does work; however this is an energetically excited state for many products and as such it needs to be stabilized in order to be delivered consistently and with improved solubility.
Moving to chemical modification the salt form of the drug product is an obvious step. Ibuprofen highlights this most simply for any reader. First came the free acid with a solubility quoted as 21 mg/l. If we then look at Sodium Ibuprofen (Ibuprofen sodium salt), we can now see statements of solubility at 100 mg/ml, though the solution may be slightly hazy. However, this is a dramatic improvement in solubility. Finally there is Ibuprofen lysinate with a quoted solubility of 17% (BASF, racemic Ibuprofen lysine). Each stage of the evolution of this drug product is yielding ever better solubility, and as such more delivery options.
Finally I would like to highlight complexation as a means to improve aqueous solubility. The use of cyclodextrins has been well reported, but not well utilized. I am starting to see movement in this area for pharma and nutra applications and expect it to grow as the need expands in the marketplace.
SC: From among the techniques described in question 3, SPI Pharma has worked on solid dispersion in aqueous media with model API’s like Finofibrate demonstrating in-vitro dissolution data equal to or better than that of nano particle systems. As it is well known, the nano technology is very expensive and poses challenges in stabilizing the slurry, whereas the proprietary technology developed by SPI Pharma to enhance the solubility of Class II and Class IV API’s involves a cost-effective aqueous process with proprietary ingredients. SPI plans to conduct pilot pK, a 3-way cross-over study to compare the regular product against the nano technology and SPI’s technology.
SA: The conventional approaches to increase the solubility of an API are: (i) micromilling/micronization, (ii) prodrug, (iii) pH modification and (iv) salt formation, and the non-conventional approaches are: (a) solid dispersions including hot melt extrusion (HME) and spray drying, among others, and self-emulsifying drug delivery systems (SEDDS/SMEDDS). Of the conventional approaches, the salt formation is widely used due, in part, to the availability of a range of inorganic and organic acids, which could increase the stability while increasing the solubility of an API in salt form. While these conventional approaches are simple and applied more frequently, their development could be challenging when designing a medium to high dosage products. For such dosages, the non-conventional approaches are highly preferred.
What are the challenges of orally delivering macromolecular drugs?
RL: The significant challenges of delivering drugs like proteins and peptides as well as other macromolecules via oral administration stem from various factors, including their proneness to degradation, their suboptimal physicochemical properties for the permeation of biological membranes, and specific therapeutic requirements with respect to onset of action, therapeutic window, and duration of action. Degradation is a severely limiting factor given that the pharmacological activity of proteins is largely dependent on their intact primary, secondary, tertiary, and quaternary structure. The numerous degradation pathways, both physical and chemical, include denaturation, aggregation, precipitation, and adsorption as well as oxidation, deamination peptide cleavage, disulfide formation, and cyclization among others. Hence it is difficult to achieve the intact passage of the GI tract for many macromolecular drugs. Given their size and polarity, many macromolecules cannot cross relevant biological barriers like mucus, glycocalyx, and cell membranes at the required flux rates. Taken together, these challenges result in the fact that most macromolecular drugs only have a very limited bioavailability, which in some cases increases the cost of goods of a drug product so far that the overall cost of a potential therapy becomes unaffordable. In addition, their bioavailbility often is very variable upon oral administration, which is specifically problematic for those drugs which have a narrow therapeutic window.
All that being said, the field of non-invasive macromolecular drug delivery is of greatest importance today, given the rich portfolios of macromolecular drugs under current development and their therapeutic potential, which cannot always be maximized by standard routes of invasive delivery. Overcoming the aforementioned oral delivery challenges holds significant promise for the optimization of therapies and improving patient outcomes in the future.
HC: Macromolecular drugs have high molecular weight and usually require novel drug delivery systems for enhancing their absorption. Further, it’s very difficult to control their in vivo metabolism and in vivo distribution for adequate targeting to delivery sites.
SA: Encapsulation and delivery of macromolecules have been challenging, and the industry is addressing these challenges by developing the nanoparticulates susceptible to higher drug loading, but unsusceptible to prevent enzymatic degradation. Therefore, there is a continued interest to improve the stability of macromolecules in the gastrointestinal tract.