Strategies and industrial perspectives to improve oral absorption of biological macromolecules

Introduction: Therapeutic proteins have become a highly attractive drug of choice due to minimal toxicity, high activity and exquisite specificity. Oral delivery of protein drugs is a very interesting area for research, and, naturally, numerous technologies are required to improve the oral bioavailability of therapeutic proteins.

Areas covered: This review article systemically generalized the major physiological barriers facing oral macromolecule delivery as well as the current approaches and novel developments in the field, including permeation enhancers, enzyme inhibitors, particulate drug delivery system, ligand delivery system, mucoadhesive delivery system, mucus penetration delivery system and other strategies.

Expert opinion: The development of composite formulation methods need to meet regulatory requirements for reproducibility, manufacturing cost, and bioavailability. So far, oral delivery of protein and peptide drugs is still facing immense challenges despite of the fact that some clinical studies are undergoing. The most advanced clinical strategies for therapeutic proteins are co-administration of absorption enhancers or protease inhibitors. Besides, rising new technologies in the field also provides a growing opportunity, such as nanotechnology, mucoadhesive and mucus penetration particulate delivery system.     

Extended-release drug formulations for the treatment of epilepsy

Introduction: Extended-release (ER) preparations are either available or have been tested for several antiepileptic drugs (AEDs). Indeed, they may be helpful in improving efficacy, tolerability, adherence, compared to the corresponding immediate release (IR) preparations available. The use of ER preparations has been advocated in women of childbearing age and is – depending on the drug – especially helpful in patients who are treated in combination with enzyme inducing AEDs as well as in children.

Areas covered: Clinical and pharmacokinetic studies on ER formulations of AEDs were identified by a PubMed literature research. Further references were added from the authors’ personal knowledge and from the reference lists of the identified studies. Reviews and expert commentaries were included, where necessary.

Expert opinion: Unfortunately, studies providing direct comparisons of ER and IR formulations of a given drug are only available for a handful of drugs. ER preparations are especially helpful in drugs with a short elimination half-life and concentration-depending efficacy and tolerability.     

Paliperidone for the treatment of schizophrenia and schizoaffective disorders - a drug safety evaluation

Introduction: Paliperidone, the major active metabolite of risperidone, is a second-generation antipsychotic that has been developed as an extended-release (ER) oral formulation and a long-acting injectable paliperidone palmitate (PP) formulation. Paliperidone has demonstrated efficacy in the reduction of acute schizophrenia symptoms and clinical benefits were maintained also in the long-term treatments. Paliperidone ER and PP are generally well tolerated with a predictable adverse event profile.

Areas covered: Data from studies evaluating safety and tolerability in the acute and maintenance treatment of schizophrenia with paliperidone are reviewed. The reported treatment-emergent adverse events of these formulations are discussed.

Expert opinion: In the treatment of schizophrenia and schizoaffective disorders the safety profile has a central role because it can enhance patient compliance. In fact treatment-emergent adverse events are one of the main causes of discontinuation in these patients. In particular the main limitation in the administration of paliperidone could be represented by the onset of hyperprolactinemia (especially in women) and of mild parkinsonism. Paliperidone has a high impact on current long-term drug strategies, especially given the new 3 month long-acting injectable formulation of PP.     

Recent advances in drug delivery via the organic cation/carnitine transporter 2 (OCTN2/SLC22A5)

Introduction: Transporters in the plasma membrane have been exploited successfully for the delivery of drugs in the form of prodrugs and nanoparticles. Organic cation/carnitine transporter 2 (OCTN2, SLC22A5) has emerged as a viable target for drug delivery. OCTN2 is a Na⁺-dependent high-affinity transporter for L-carnitine and a Na⁺-independent transporter for organic cations. OCTN2 is expressed in the blood-brain barrier, heart, liver, kidney, intestinal tract and placenta and plays an essential role in L-carnitine homeostasis in the body.

Areas covered: In recent years, several studies have been reported in the literature describing the utility of OCTN2 to enhance the delivery of drugs, prodrugs and nanoparticles. Here we summarize the salient features of OCTN2 in terms of its role in the cellular uptake of its physiological substrate L-carnitine in physiological and pathological context; the structural requirements for recognition and the recent advances in OCTN2-targeted drug delivery systems, including prodrugs and nanoparticles, are discussed.

Expert opinion: This transporter has great potential to be utilized as a target for drug delivery to improve oral absorption of drugs in the intestinal tract. It also has potential to facilitate the transfer of drugs across the biological barriers such as the blood-brain barrier, blood-retinal barrier, and maternal-fetal barrier.     

The safety of beclomethasone dipropionate in the treatment of ulcerative colitis

Introduction: Beclomethasone dipropionate (BDP) is a second-generation corticosteroid that uses novel drug technologies to ensure colonic targeting and potentially reducing systemic corticosteroid concentrations. It is approved for treatment of patients with mild-to-moderate ulcerative colitis (UC) who do not respond to mesalazine. The gut-selective mechanism of action has the potential to improve the safety profile of BDP compared with other conventional corticosteroids.

Areas covered: We reviewed the mechanism of action, efficacy, and safety of BDP in the treatment of UC. The positioning of BDP in management algorithms is also discussed.

Expert opinion: The highly selective mechanism of action of BDP restricts the steroid-related side effects. BDP is efficacious in the treatment of active UC. Topical formulation is the first choice in distal UC, while oral formulation is used in patients with an extensive involvement of the colon. The rates of adverse events (AE), serious AEs, and steroid-related side-effects are similar to placebo and mesalamine and slightly inferior to traditional corticosteroids.     

An update on the potential role of intestinal first-pass metabolism for the prediction of drug–drug interactions: the role of PBPK modeling

Introduction: The intestinal absorption process is a combination of several events that are governed by various factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. Many studies have provided clear evidence on the significant role of intestinal first-pass metabolism on drug bioavailability and degree of drug–drug interactions (DDIs).

Areas covered: This review provides an update on the role of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs. It also provides a comprehensive overview and summary of the latest update in the role of physiologically based pharmacokinetic models modeling in prediction of intestinal metabolism and DDIs in humans.

Expert opinion: The contribution of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs has become more evident over the last few years. Several in vitro, in situ, and in vivo models have been developed to evaluate the role of first-pass metabolism and to predict DDIs. Currently, physiologically based pharmacokinetic modeling is considered the most valuable tool for the prediction of intestinal first-pass metabolism and DDIs.     

Pharmacokinetic drug evaluation of extended release lorcaserin for the treatment of obesity

Introduction: Lorcaserin is a serotonin 2C receptor antagonist that was FDA approved in 2012. Lorcaserin is recently available as an extended-release (ER) formulation for the treatment of obesity as an adjunct to lifestyle modification.

Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of lorcaserin ER will be reviewed.

Expert opinion: Lorcaserin ER 20mg daily provides drug exposure bioequivalent to lorcaserin immediate release (IR) 10mg twice daily. Lorcaserin IR is associated with 3.3 and 3.0% placebo-subtracted weight loss in patients without and with diabetes, respectively. A1C was reduced by 0.9% in patients with diabetes. Common side effects include headache, dry mouth, constipation, dizziness, fatigue, and nausea. Lorcaserin provides potential advantages over other antiobesity medications in regards to tolerability and simplicity of medication initiation, but may not be as effective as other options. Lorcaserin ER offers improved ease of administration and anticipated adherence compared to the IR formulation. The place in therapy for lorcaserin ER and other antiobesity medications will be further clarified by results of pending clinical trials addressing cardiovascular outcomes as well as the role pharmacogenomics and comorbid disease states may play in choosing patient-specific therapy.     

A safety evaluation of budesonide MMX for the treatment of ulcerative colitis

Introduction: Budesonide belongs to low-bioavailability steroids class. A novel oral formulation of budesonide, which uses the Multi-Matrix System (MMX) for delivering drugs to the colon, is now available as a possible treatment of ulcerative colitis patients intolerant or not-responding to first-line therapy with 5-ASA.

Areas covered: in this review we present information about the development and the use of budesonide MMX and we provide data about its mechanism of action as well as, pharmacodynamics and pharmacokynetics. Moreover, we present the available literature data about the efficacy and, mainly, the safety of budesonide-MMX.

Expert opinion: budesonide-MMX is a new therapeutic option in mild-to-moderate UC patients. Its good safety profile in clinical trials undoubtedly represents a strength for a possible wide use in clinical practice, mainly if it will be confirmed by post-marketing data. Other indications, such as treatment of colonic Crohn’s disease, could theoretically be considered, if sustained by reliable scientific data.     

Skin penetration and tissue permeation after topical administration of diclofenac

Objective: Topical delivery of drugs is an alternative to oral administration, often with similar efficacy but potentially a more favorable tolerability profile. However, topical formulations need to be able to penetrate the skin and permeate to the target areas in quantities sufficient to exert a therapeutic effect. Many factors can affect this process, including the physicochemical properties of the drug, the formulation used, and the site and mode of application. It is believed that measurement of drug concentrations at the sites of action may be an indicator of their likely efficacy. This review addresses these issues, with reference to topically administered diclofenac in osteoarthritis.

Methods: Articles relevant to this review were identified after a systematic search of Medline and Embase, using the key words “diclofenac”, "topical administration" and “osteoarthritis” in the search strategy.

Results: The sparse data available indicate that topical diclofenac can penetrate and permeate to deeper tissues, with a lower plasma to tissue ratio than oral diclofenac. The tissue diclofenac levels after topical delivery are sustained over time (at least several hours). However, there is not enough data to establish how diclofenac levels in the joint compare with IC₅₀ levels (50% of the maximum inhibition of prostaglandin synthesis) established following oral administration.

Conclusions: After topical application, diclofenac can penetrate the skin and permeate to deeper tissues, where it reaches a concentration that appears to be sufficient to exert a therapeutic effect. More robust methods are required for in vivo characterization to better estimate the clinical efficacy of topically applied drugs.     

Clinical risks of St John’s Wort (Hypericum perforatum) co-administration

Introduction: St. John’s wort (SJW) is a common medicinal herb used for the treatment of mild to moderate depression. Hyperforin, one of the chief components of SJW, plays an important role in the induction of cytochrome P450 enzymes (CYP) and P-glycoprotein transporter (P-gp), and therefore, affects the pharmacokinetics of various drugs. There are several clinical studies demonstrating the interaction of SJW with the metabolism of conventional drugs which may cause life-threatening events.

Areas covered: This review focuses on human studies that have evaluated pharmacokinetic alterations of conventional drugs in concomitant use with different SJW preparations.

Expert opinion: SJW preparations have demonstrated clinically important interactions with several classes of conventional drugs such as immunosuppressants, anticancer agents, cardiovascular drugs, oral contraceptives, and lipid lowering agents that caused life-threatening events in several cases. The patient information label on the SJW products should provide enough information regarding the possible risk of interaction. Hyperforin seems to be the major ingredient responsible for CYP and P-gp inducing activity of SJW; thus, hyperforin-free products may be future candidates to decrease SJW’s drug interactions.     

The influence of excipients on physical and pharmaceutical properties of oral lyophilisates containing a pregabalin-acetaminophen combination

Objectives: The purpose of the study was to investigate and characterize the oral lyophilisates containing the pregabalin-acetaminophen drug combination and as xcipients mannitol with microcrystalline cellulose or hydroxypropyl methylcellulose, in order to conclude upon drug-excipient interactions and their stability implications, impact of excipients on drug release and on the physicochemical and mechanical properties of the pharmaceutical formulations.

Methods: The oral tablets were made by using a Christ freeze-dryer alpha 2–4-LSC lyophilizer, and evaluated for stability, drug-excipient compatibility and homogeneity of the prepared pharmaceutical formulations. The formulations were evaluated for in vivo absorption in rabbits by histopathological exams.

Results: FTIR and thermogravimetric analyses, DLS technique, SEM and NIR-CI studies confirmed the compatibility between compounds. From the determined physical and biochemical parameters of the formulations it was established that they are stable, homogeneous, and meet the conditions for orally disintegrating tablets.

Conclusion: In the case of the investigated pharmaceutical formulations the study evidenced the assembling through physical bonds between the excipients and the ‘codrug’ complex, which do not affect the release of the bioactive compounds.     

Solid lipid nanocarriers in drug delivery: characterization and design

Introduction: Solid lipid nanoparticles are promising drug carriers for systemic circulations as well as local applications. One of the major challenges for drug delivery is designing nanocarriers for efficient delivery of active substances to the target site and facilitating drug absorption.

Areas covered: In this article, the effects of excipients and particle preparation methods on the properties of solid lipid nanocarriers (SLNCs) and their impact on drug absorption and efficacies related to different administration routes are reviewed and discussed.

Expert opinion: SLNCs have special characteristics, making them attractive as drug delivery systems, for parenteral and oral delivery for systemic effects, or ocular, pulmonary and topical delivery to enhance local treatment efficacy and reducing systemic side effects. Both excipients and fabrication methods are crucial for the function and size of nanoparticles and should be considered simultaneously in designing particles to obtain the optimal drug absorption and efficacy, especially for local treatments. Despite the demonstrated advantages by the preclinical studies, further studies on improved understanding of the interactions of SLNCs with biological tissues of the target site is necessary for efficient designing functional nanoparticles for clinical applications.

Abbreviations: DG: diglycerides; FFA: free fatty acids; GMS: glyceryl monostearate; MG: monoglycerides; NLC: nanostructured lipid carriers; PL: phospholipids; SLM: solid lipid microparticles; SLN: solid lipid nanoparticles; SLNC: solid lipid nanocarriers; TG: triglycerides.     

From nanoemulsions to self-nanoemulsions,with recent advances in self-nanoemulsifying drug delivery systems (SNEDDS)

Introduction: Lipid-based drug delivery systems (LBDDS) are the most promising technique to formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic performance of hydrophobic drugs and has become an essential approach in drug delivery research. Self-nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the formulation of drugs with poor aqueous solubility.

Areas covered: The review in its first part shortly describes the LBDDS, nanoemulsions and clarifies the ambiguity between nanoemulsions and microemulsions. In the second part, the review discusses SNEDDS and elaborates on the current developments and modifications in this area without discussing their associated preparation techniques and excipient properties.

Expert opinion: SNEDDS have exhibit the potential to increase the bioavailability of poorly water soluble drugs. The stability of SNEDDS is further increased by solidification. Controlled release and supersaturation can be achieved, and are associated with increased patient compliance and improved drug loads, respectively. Presence of biodegradable ingredients and ease of large-scale manufacturing combined with a lot of ‘drug-targeting opportunities’ give SNEDDS a clear distinction and prominence over other solubility enhancement techniques.     

Drug delivery of oral anti-cancer fluoropyrimidine agents

Introduction: Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules.

Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs.

Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.     

Use of in vitro performance models in the assessment of drug delivery across the human nail for nail disorders

Introduction: Onychomycosis is the most prevalent nail condition, affecting between 5% and 20% of the population in western countries. Oral therapies are not the treatment of choice due to poor patient compliance, high relapse rates, severe side effects, and contraindication. However, the difficultly in curing the condition using topical delivery is partly due to both the nail structure presenting a complex barrier and the lack of understanding of how best to achieve delivery of drug to the nail bed.

Areas covered: Several novel in vitro models incorporating human nails discussed in this article have been developed in recent years that allow for the study of the mechanisms of ungual drug absorption and formulation efficacy to be assessed.

Expert opinion: The TurChub zone of inhibition model is a high-throughput performance screen for prototype formulations during development, while the robustness of the ChubTur nail permeation, TurSh nail penetration, and RoMar antifungal efficacy models ensure these can be validated for in vitro bioequivalence testing of generic products to reference listed drugs. With clinical trials being a costly and high-risk approach to generic approval, the described novel in vitro screening and performance testing techniques offer a de-risked and less-expensive route to market.     

Advancements in the treatment of hypothyroidism with L-T4 liquid formulation or soft gel capsule: an update

Introduction: The most recent advance concerning levothyroxine (L-T4) therapy is the development of novel oral formulations: the liquid preparation, and the soft gel capsule.

Areas covered: This review evaluates the most recent clinical studies about these new formulations. The liquid formulation has been shown to overcome: the food and beverages intereference with L-T4 tablets absorption, caused by food or coffee at breakfast; malabsorption induced by the increased gastric pH, resulting from atrophic gastritis, or due to proton-pump inhibitors; and malabsorption after bariatric surgery. The use of liquid L-T4 has been studied also in pregnancy, newborns and infants, suggesting a better bioequivalence than tablets. Finally, liquid L-T4 is more active than tablets in the control of thyroid-stimulating hormone (TSH) in hypothyroid patients without malabsorption, drug interference, or gastric disorders, leading to a hypothesized higher absorption of liquid L-T4 also in these patients. Few studies have evaluated soft gel L-T4 with promising results in patients with malabsorption related to coffee or gastritis.

Expert opinion: Liquid L-T4 (and soft gel capsules) are more active than the tablet L-T4 in the control of TSH in hypothyroid patients with gastric disorders, malabsorption, or drug interference, but also in patients without absorption disorders.     

Influence of route of administration/drug formulation and other factors on adherence to treatment in rheumatoid arthritis (pain related) and dyslipidemia (non-pain related)

Objectives: A comprehensive review was performed to investigate the effect of route of administration on medication adherence and persistence in rheumatoid arthritis (RA) and to compare adherence/persistence with oral medications between RA and a non-painful disease (dyslipidemia).

Research design and methods: Comprehensive database searches were performed to identify studies investigating medication adherence and/or persistence in adults with RA receiving conventional synthetic or biologic agents. Similar searches were performed for studies of patients with dyslipidemia receiving statins. Studies had to be published after 1998 in English and involve ≥6 months’ follow up.

Main outcome measures: Adherence and persistence were compared between the different routes of drug administration in RA, and between the two diseases for oral medications.

Results: A total of 35 and 28 papers underwent data extraction for RA and dyslipidemia, respectively. Within the constraints of the analysis, adherence and persistence rates appeared broadly similar for the different routes of drug administration in RA. Adherence to oral medications was also broadly similar across the two diseases, but persistence was lower in dyslipidemia. Poor adherence has clinical consequences in both diseases: greater disease activity and risk of flare in RA, and increased serum cholesterol levels and risk of heart and cerebrovascular disease in dyslipidemia. Over 1–3 years, poor adherence to biologic RA medications led to increased resource use and medical costs but lower total direct costs due to reduced biologic drug costs. Conversely, poor adherence to dyslipidemia medications resulted in increased total direct costs. In both diseases, adherence improved with patient education/support.

Conclusions: The route of drug administration and the symptomatic (pain) nature of the disease do not appear to be dominant factors for drug adherence or persistence in RA.

Limitation: The wide range of adherence and persistence values and definitions across studies made comparisons between drug formulations and diseases difficult.     

The role of organic anion transporting polypeptides in drug absorption,distribution, excretion and drug-drug interactions

Introduction: The in vivo fate and effectiveness of a drug depends highly on its absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Organic anion transporting polypeptides (OATPs) are membrane proteins involved in the cellular uptake of various organic compounds, including clinically used drugs. Since OATPs are significant players in drug absorption and distribution, modulation of OATP function via pharmacotherapy with OATP substrates/inhibitors, or modulation of their expression, affects drug pharmacokinetics. Given their cancer-specific expression, OATPs may also be considered anticancer drug targets.

Areas covered: We describe the human OATP family, discussing clinically relevant consequences of altered OATP function. We offer a critical analysis of published data on the role of OATPs in ADME and in drug–drug interactions, especially focusing on OATP1A2, 1B1, 1B3 and 2B1.

Expert opinion: Four members of the OATP family, 1A2, 1B1, 1B3 and 2B1, have been characterized in detail. As biochemical and pharmacological knowledge on the other OATPs is lacking, it seems timely to direct research efforts towards developing the experimental framework needed to investigate the transport mechanism and substrate specificity of the poorly described OATPs. In addition, elucidating the role of OATPs in tumor development and therapy response are critical avenues for further research.     

Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs

Introduction: The major challenge of first pass metabolism in oral drug delivery can be surmounted by directing delivery toward intestinal lymphatic system (ILS). ILS circumvents the liver and transports drug directly into systemic circulation via thoracic duct. Lipid and polymeric nanoparticles are transported into ILS through lacteal and Peyer’s patches. Moreover, surface modification of nanoparticles with ligand which is specific for Peyer’s patches enhances the uptake of drugs into ILS. Bioavailability enhancement by lymphatic uptake is an advantageous approach adopted by scientists today. Therefore, it is important to understand clear insight of ILS in targeted drug delivery and challenges involved in it.

Areas covered: Current review includes an overview of ILS, factors governing lymphatic transport of nanoparticles and absorption mechanism of lipid and polymeric nanoparticles into ILS. Various ligands used to target Peyer’s patch and their conjugation strategies to nanoparticles are explained in detail. In vitro and in vivo models used to assess intestinal lymphatic transport of molecules are discussed further.

Expert opinion: Although ILS offers a versatile pathway for nanotechnology based targeted drug delivery, extensive investigations on validation of the lymphatic transport models and on the strategies for gastric protection of targeted nanocarriers have to be perceived in for excellent performance of ILS in oral drug delivery.