Current Pharmaceutical Biotechnology - Volume 15, Issue 7, 2014

Diabetes mellitus is a chronic disease that occurs either when the pancreas does not produce enough insulin and /or when the body became resistant to insulin actions. Type 1 diabetes (T1DM) (previously known as insulin-dependent, juvenile or childhood-onset) is characterized by an almost complete loss of insulin mainly due to selective autoimmune destruction of the pancreatic β-cells and requires daily administration of insulin. Type 2 diabetes (T2DM) (formerly called non-insulin-dependent or adult-onset) results from insulin resistance and deterioration and βcell function. T2DM comprises 90% of people with diabetes around the world, and is largely related to excess body weight and physical inactivity. Gestational diabetes is hyperglycemia that starts or is firstly diagnosed during pregnancy. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are intermediate conditions in the transition between normality and diabetes. People with IGT or IFG are at high risk of progressing to T2DM, although this is not inevitable. Other specific are associated with endocrinopathies, exocrine pancreas disease, genetic defects of the β-cell or in insulin action has been given [1]. The therapy of T2DM is currently based on 6 approved drug classes encompassing both small molecules [metformin, sulfonylureas, glitazones, dipeptidyl peptidase-4 (DPP-IV) inhibitors] and proteins [insulin and analogues, glucagon-like polypeptide- I (GLP-1) and analogues]. Insulin and analogues are potentially administrated by parenteral route, which generally requires multiple daily injections, not contributing to improve the quality of life of diabetics. To eliminate the pain and fear associated with injections and increase diabetics compliance, intense research has been done towards alternative routes that are painless and non-invasive. Generally, drugs delivered by oral route improves disease management, increase patient compliance and reduces the risk of most diabetes-related complications. However, therapeutic drugs such as peptides and proteins need to overcome critical hurdles, namely the passage along the gastrointestinal tract and the transport across intestinal epithelial cells, prior to their beneficial systemic action. Nanotechnology has opened the possibility of increasing the stability of peptides and proteins and their bioavailability as well. The development of nanoparticulate delivery systems for insulin has evolved through remarkable advances hardly seen in the field of drug delivery. Thus, the present thematic is divided into three main sections addressing the treatment of Diabetes. T1DM, has been treated by successful transplantation of insulin secreting pancreatic islets. However, serious limitations remain such as the requirement of immunosuppressive drugs for recipient patients, serious side effects as a result of long term use of drugs, and reduced functionality of islets at the transplantation site. The use of bioartificial pancreas may be a potentially valid alternative. The Kizikel’s group addressed current progress and obstacles for the development of a bioartificial pancreas using micro- and nano based systems for encapsulation of islets. T2DM is one of the most prevalent and rapidly spreading diseases worldwide. The incretin based therapies for T2DM are now widely investigated and used, and mainly include incretin hormones which are glucose-dependent insulinotropic peptide (GIP) and GLP-1 released from the endocrinal cells in small intestine in response to food intake. Araujo et al. highlighted the use of micro and nanosystems to efficiently deliver the incretins orally. T2DM is a progressive disease, and most patients, as it happens in T1DM, will eventually need treatment with exogenous insulin. The therapeutic goal of the treatment with insulin is to reproduce, as accurately as possible, the physiological pattern of insulin secretion, in order to control glycemia. In former times, the emphasis of oral delivery of insulin was more on convenience and avoidance of needles. Taking into account the current understanding of the pathogenesis of diabetes, additional emphasis has been given to the oral delivery of insulin as the most physiological mimicking way to deliver exogenous insulin to its site(s) of action in the target tissues and cells. The third section includes two articles that discuss different barriers encountered by insulin nanoparticles in the gastrointestinal tract and nanosystems being used for oral delivery for insulin toward clinical trials and industrial development, respectively. Lopes at al. speculated about the role of nanoparticles in the insulin transport across intestinal epithelium, besides explore their likely pathways and analyze published experimental results on the bioavailability (BA) and pharmacological activity (PA) of oral insulin. Cabral’s group described nanosystems that provide oral insulin release, and mitigated advantages ascribed to those nanosystems with evident economic and industrial feasibility.

Type I diabetes mellitus (TIDM), a devastating health issue in all over the world, has been treated by successful transplantation of insulin secreting pancreatic islets. However, serious limitations such as the requirement of immunosuppressive drugs for recipient patients, side effects as a result of long-term use of drugs, and reduced functionality of islets at the transplantation site remain. Bioartificial pancreas that includes islets encapsulated within semi-permeable membrane has been considered as a promising approach to address these requirements. Many studies have focused on micro or nanobased islet immunoisolation systems and tested the efficacy of encapsulated islets using in vitro and in vivo platforms. In this review, we address current progress and obstacles for the development of a bioartificial pancreas using micro/nanobased systems for encapsulation of islets.

Type 2 diabetes mellitus (T2DM) is mainly associated with impaired insulin secretion by the pancreatic β-cells, insulin resistance and elevated hepatic gluconeogenesis. Incretin based treatments for T2DM are now widely investigated and used. The incretin based therapies mainly include incretin hormones which are glucose-dependent insulinotropic peptides (GIP) and glucagon like peptide-1 (GLP-1) released from the endocrinal cells in the small intestine in response to food intake. The main function of GLP-1 is to induce insulin secretion and suppress glucagon secretion. This review describes the different formulation approaches for oral delivery of incretins and the limitations associated with this route of administration. We highlight the use of micro and nanosystems to efficiently deliver the incretins orally. Furthermore, we present several examples of the significant potential of these systems in pharmaceutical applications.

The treatment of Diabetes Mellitus (DM), a chronic disease, is primarily based upon administration of insulin forms to patients. Conventional subcutaneous administration is associated with a large number of complications, therefore, several new strategies have been developed. Amongst these strategies, oral insulin administration is much less invasive and, therefore, well tolerated. In recent years, various nanoformulations were developed for the oral administration of insulin, allowing more effective stabilization of the active pharmaceutical ingredient and modified for better absorption along the gastrointestinal tract. The development of different oral insulin nanoformulations in academic research as well as in patents, including the development of nanoparticles, liposomes, nanoemulsions and the use of cyclodextrins deserves special attention. The future of oral insulin nanoformulations is dependent on strategies utilizing simple technologies that stabilize the raw material, including inclusion within cyclodextrins or inclusion in low weight molecular mass polymers/ oligomers. All of the theories developed here provide a solid foundation upon which to develop new methods for the production of pharmaceutical peptide formulations. In addition, the effective search for existing nanometric formulations of insulin could provide economically viable therapeutic options that can consequently be produced on an industrial scale.

The oral route is the most suitable and physiological delivery route. Oral insulin delivery would minimize the health hazard implied in repeated injection, surpass complications arising from the need for sterile techniques associated with parenteral formulations and provide better glucose homeostasis. However, it is limited by various physiological barriers and still remains a scientific challenge. The desire to deliver insulin by the oral route in a conveniently and effectively way has led to the intense investigation of new delivery systems. Nanodelivery systems have been proposed to enhance the bioavailability of insulin after oral administration. This review article describes the gastrointestinal barriers to oral insulin delivery, including chemical, enzymatic and absorption barriers. The potential transport mechanisms of insulin delivered by nanoparticles across the intestinal epithelium are also addressed. Finally, how nanoparticles characteristics affect insulin pharmacological activity and bioavailability is discussed.

Biotechnology has provided a wide array of therapeutic agents such as peptide, protein, vaccine and gene products that are currently mainly administered by means of injections. Therapeutic agents produced by biotechnological processes such as recombinant DNA technology, fermentation, tissue and cell culture technology as well as genetic engineering are usually large, hydrophilic molecules facing delivery challenges, for example, these drugs are susceptible to degradation and are generally poorly membrane permeable. Since successful delivery of any drug is a pre-requisite to achieve the therapeutic goal, novel strategies have emerged in the late 20th century to overcome challenges associated with the oral route of drug administration. These strategies include, but are not restricted to micro- and nanotechnology including self-emulsifying lipid based formulations, dendrimers and devices, permeability enhancing technology, targeting of active transporters and membrane receptors, use of cell penetrating peptides, chemical modifications of peptides such as inclusion complex formation and peptide conjugates, site-specific delivery systems, muco-adhesive systems and polymeric hydrogels. Despite the initial excitement regarding the potential of these technologies to provide effective oral delivery, few have advanced from the pre-clinical stage into clinical trials and very few, if any, resulted so far in registered medicinal products. Moreover, most literature provides information on effectiveness and mechanisms based on in vitro investigations without revealing the viability of these technologies in clinical practice. Although this topic of oral peptide delivery has gone through different phases in terms of attracting attention from the scientific community, it remains a timely research subject. The therapeutic benefits to patients and potential economic benefits to the producer serve as the driving forces behind finding an effective oral delivery system for biotechnology derived drugs. This special issue aims at assessing some of the latest developments in the field of oral delivery of biotechnological therapeutic agents. The reader will not only gain an understanding of the challenges associated with oral delivery of protein and peptide based drugs, but certain strategies that emerged to overcome these drawbacks are also discussed. From the discussions it is clear that scientific research has contributed to a deeper understanding of older drug delivery strategies, while new discoveries keep the vision of producing an effective oral peptide drug delivery system alive.

Anticoagulant therapy is widely used for the treatment and prophylaxis of deep vein thrombosis and coronary syndromes. Until now, drugs such as unfractionated heparin and low molecular weight heparins need to be administered parenterally. Parenteral administration results in lower patient compliance compared to oral therapy and for this reason, the focus of various research groups is to develop an oral heparin formulation which is as effective as the parenteral formulation, easy to use and non-toxic. In the last few years, some new oral anticoagulants like Rivaroxaban (Xarelto®), Apixaban (Eliquis®) and Dabigatranetexilat (Pradaxa®) have reached the market, but their use is limited to certain indications. Therefore, the development of oral formulations with well-established anti-coagulant drugs is still relevant and in demand. In this paper, we reviewed strategies that have been developed so far to achieve an adequate anticoagulant effect using oral formulations of unfractionated and low molecular weight heparins.

Biotechnology has been used for a long period of time in the most diverse scientific areas, making its journey in close contact with pharmaceutical sciences. Among the several products manufactured in biotechnological industry, peptides and proteins are in the front-line for the treatment of several diseases due to their selectivity, effective action and few side effects. However, orally administration route is not feasible for peptide and protein drugs due to the several physical and chemical barriers along the gastrointestinal tract and, consequently, are delivery by parental routes. Between several strategies, it is believed that delivery systems can render the oral route viable, increasing the convenience and compliance of patients and enhancing drugs therapeutic effect. Recently, more specific strategies have been explored to better direct the delivery systems, achieved by their functionalization with ligands that specifically bind to membrane transporters and receptors existing along the gastrointestinal way. Despite the promising results obtained with functionalized nanoparticles, the oral delivery of peptides/proteins is still limited and a lot of research is required to successfully introduce nanoparticles in the clinical field.

In the last decades several new biotechnologically-based therapeutics have been developed due to progress in genetic engineering. A growing challenge facing pharmaceutical scientists is formulating these compounds into oral dosage forms with adequate bioavailability. An increasingly popular approach to formulate biotechnology-based therapeutics is the use of lipid based formulation technologies. This review highlights the importance of lipid based drug delivery systems in the formulation of oral biotechnology based therapeutics including peptides, proteins, DNA, siRNA and vaccines. The different production procedures used to achieve high encapsulation efficiencies of the bioactives are discussed, as well as the factors influencing the choice of excipient. Lipid based colloidal drug delivery systems including liposomes and solid lipid nanoparticles are reviewed with a focus on recent advances and updates. We further describe microemulsions and self-emulsifying drug delivery systems and recent findings on bioactive delivery. We conclude the review with a few examples on novel lipid based formulation technologies.

The oral route is the most convenient and least expensive route of drug administration. Yet, it is accompanied by many physiological barriers to drug uptake including low stomach pH, intestinal enzymes and transporters, mucosal barriers, and high intestinal fluid shear. While many drug delivery systems have been developed for oral drug administration, the physiological components of the gastro intestinal tract remain formidable barriers to drug uptake. Recently, microfabrication techniques have been applied to create micron-scale devices for oral drug delivery with a high degree of control over microdevice size, shape, chemical composition, drug release profile, and targeting ability. With precise control over device properties, microdevices can be fabricated with characteristics that provide increased adhesion for prolonged drug exposure, unidirectional release which serves to avoid luminal drug loss and enhance drug permeation, and protection of a drug payload from the harsh environment of the intestinal tract. Here we review the recent developments in microdevice technology and discuss the potential of these devices to overcome unsolved challenges in oral drug delivery.