pH- and ion-sensitive polymers for drug delivery

Introduction: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.

Areas covered: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.

Expert opinion: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.     

Advances in oral macromolecular drug delivery

Introduction: Various macromolecules including polypeptides, proteins, genes and polysaccharides have been drawing attention for their therapeutic potential. The passage through intestinal epithelium is the major barrier for the oral delivery of macromolecules, by either paracellular or transcellular pathways. However, most macromolecules are poorly absorbed in oral route due to their high molecular weight and low stability in the gastrointestinal (GI) tract. Nonetheless, advancing in oral macromolecular drug delivery will be significant in expanding the clinical use of therapeutic macromolecules.

Areas covered: Technologies using chemical conjugation, absorption enhancers and nano-/micro-particulate systems have been developed to improve oral bioavailability of macromolecules, and some of them are in the process of clinical trials. In this review, they are discussed in the context of their progression states, hurdles and modes of action.

Expert opinion: According to the better understanding of receptor or transporter structure and transport mechanisms in the GI tract, the progress ineffective oral delivery systems for therapeutic macromolecules is anticipated over the next decades. In addition, the advent of numerous particulate systems will also speed up the development of novel drug delivery technologies. This offers an optimistic perspective on the potential clinical usage of oral macromolecular drugs.     

Utilization of nanoemulsions to enhance bioactivity of pharmaceuticals,supplements, and nutraceuticals: Nanoemulsion delivery systems and nanoemulsion excipient systems

ABSTRACT

Introduction: The efficacy of many hydrophobic bioactives (pharmaceuticals, supplements, and nutraceuticals) is limited due to their relatively low or highly variable bioavailability. Nanoemulsions consisting of small lipid droplets (r < 100 nm) dispersed in water can be designed to improve bioavailability.

Areas covered: The major factors limiting the oral bioavailability of hydrophobic bioactive agents are highlighted: bioaccessibility, absorption and transformation. Two nanoemulsion-based approaches to control these processes and improve bioavailability are discussed: nanoemulsion delivery systems (NDS) and nanoemulsion excipient systems (NES). In NDS, hydrophobic bioactives are dissolved within the lipid phase of oil-in-water nanoemulsions. In NES, the bioactives are present within a conventional drug, supplement, or food, which is consumed with an oil-in-water nanoemulsion. Examples of NDS and NES utilization to improve bioactive bioavailability are given.

Expert opinion: Considerable progress has been made in nanoemulsion design, fabrication, and testing. This knowledge facilitates the design of new formulations to improve the bioavailability of pharmaceuticals, supplements, and nutraceuticals. NDS and NES must be carefully designed based on the major factors limiting the bioavailability of specific bioactives. Research is still required to ensure these systems are commercially viable, and to demonstrate their safety and efficacy using animal and human feeding studies.     

Utilizing food effects to overcome challenges in delivery of lipophilic bioactives: structural design of medical and functional foods

Introduction: The oral bioavailability of many lipophilic bioactives, such as pharmaceuticals and nutraceuticals, is relatively low due to their poor solubility, permeability and/or chemical stability within the human gastrointestinal tract (GIT). The oral bioavailability of lipophilic bioactives can be improved by designing food matrices that control their release, solubilization, transport and absorption within the GIT.

Areas covered: This article discusses the challenges associated with delivering lipophilic bioactive components, the impact of food composition and structure on oral bioavailability and the design of functional and medical foods for improving the oral bioavailability of lipophilic bioactives.

Expert opinion: Food-based delivery systems can be used to improve the oral bioavailability of lipophilic bioactives. There are a number of potential advantages to delivering lipophilic bioactives using functional or medical foods: greater compliance than conventional delivery forms; increased bioavailability and efficacy; and reduced variability in biological effects. However, food matrices are structurally complex multicomponent materials and research is still needed to identify optimum structures and compositions for particular bioactives.     

Drug delivery strategies for therapy of visceral leishmaniasis

Importance of the field: Visceral leishmaniasis (VL) is the most overwhelming type of leishmaniasis associated with the poverty of developing countries and usually mortal if untreated. Most of the conventionally used dosage forms offer us the shortcomings of toxic side effects and emergence of drug resistance. Several efforts have been made to overcome the barriers involved in the treatment of VL. Colloidal carriers extensively represent the drug delivery systems (DDSs) for intracellular localization of antileishmanial compounds in macrophage-rich organs such as liver, spleen and bone marrow. These DDSs offer superior therapeutic efficacy over the conventional treatment in terms of site-specific drug delivery with reduced side effects. However, after 35 years of research in the field, AmBisome^® (Amphotericin B liposome for injection, Astellas Pharma US, Inc.) is the only DDS used against the VL.

Areas covered in this review: A literature search was performed (for drugs and DDSs against VL) on PubMed and through Google.

What the reader will gain: This review aims to describe the pathophysiology of VL and its current conventional treatment with special reference to DDSs designed against VL.

Take home message: On reviewing the conventional drugs and DDSs developed against VL, it is concluded that advances in the field of targeted drug delivery can result in more efficient strategies for the therapy of VL.     

Mesoporous carbon nanomaterials in drug delivery and biomedical application

Abstract

Recent development of nano-technology provides highly efficient and versatile treatment methods to achieve better therapeutic efficacy and lower side effects of malignant cancer. The exploration of drug delivery systems (DDSs) based on nano-material shows great promise in translating nano-technology to clinical use to benefit patients. As an emerging inorganic nanomaterial, mesoporous carbon nanomaterials (MCNs) possess both the mesoporous structure and the carbonaceous composition, endowing them with superior nature compared with mesoporous silica nanomaterials and other carbon-based materials, such as carbon nanotube, graphene and fullerene. In this review, we highlighted the cutting-edge progress of carbon nanomaterials as drug delivery systems (DDSs), including immediate/sustained drug delivery systems and controlled/targeted drug delivery systems. In addition, several representative biomedical applications of mesoporous carbon such as (1) photo-chemo synergistic therapy; (2) delivery of therapeutic biomolecule and (3) in vivo bioimaging are discussed and integrated. Finally, potential challenges and outlook for future development of mesoporous carbon in biomedical fields have been discussed in detail.     

Solid lipid nanoparticles: an oral bioavailability enhancer vehicle

Introduction: The therapeutic efficacy of perorally administered drugs is often obscured by their poor oral bioavailability (BA) and low metabolic stability in the gastrointestinal tract (GIT). Solid lipid nanoparticles (SLNs) have emerged as potential BA enhancer vehicles for various Class II, III and IV drug molecules.

Area covered: This review examines the recent advancements in SLN technology, with regards to oral drug delivery. The discussion critically examines the effect of various key constituents on SLN absorption and their applications in oral drug delivery. The relationship between the complexity of absorption (and various factors involved during absorption, including particle size), stability and the self-emulsifying ability of the lipids used has been explored.

Expert opinion: The protective effect of SLNs, coupled with their sustained/controlled release properties, prevents drugs/macromolecules from premature degradation and improves their stability in the GIT. An extensive literature survey reveals that direct peroral administration of SLNs improves the BA of drugs by 2- to 25-fold. Overall, the ease of large-scale production, avoidance of organic solvents and improvement of oral BA make SLNs a potential BA enhancer vehicle for various Class II, III and IV drugs.     

Biodegradable synthetic polyesters in the technology of controlled dosage forms of antihypertensive drugs – the overview

ABSTRACT

Introduction: Arterial hypertension is a disease of civilization that requires long-term treatment. Recently, growing interest in natural and synthetic polymers as drug delivery vehicles in controlled release dosage forms for improving the efficacy of treatment has been observed.

Areas covered: This review introduces biodegradable synthetic polyesters as macromolecular carriers of antihypertensive drugs. Although various, synthetic and natural polymer-drug conjugates and/or polymeric carriers of anticancer drugs are currently under preclinical and clinical studies, there is no such data for antihypertensive drugs. Therefore, it seems appropriate to use such materials for the treatment of hypertension.

Expert opinion: There are currently only a few studies describing the use of synthetic polyesters in the arterial hypertension therapy. In order to the fact that there is a high demand for new, effective antihypertensive dosage forms, further studies for such drug carriers are certainly expected. Synthetic polyester carriers could improve the drug bioavailability and its pharmacokinetic properties by altering the pharmaceutical dosage form. This property is particularly useful for drugs with proven pharmacological action, but with limited application due to their inappropriate pharmacological properties. The development of new polymeric materials and technologies affords the opportunity to produce novel synthetic polyester DDSs.     

Effects of borneol on the pharmacokinetics of 9-nitrocamptothecin encapsulated in PLGA nanoparticles with different size via oral administration

Context: Although nanocarriers provide promising potential for oral drug delivery, the delivery efficiency remains unsatisfactory and needs to be improved. Size is considered to be the most important characteristic of nanoparticles related to their oral absorption. Borneol has been proved to have the ability to enhance the penetration and transport of many drugs through various physical barriers.

Objective: To investigate the effect of the particle size and coadministration of borneol on the pharmacokinetics and bioavailability of entrapped drug in different size poly(lactic-co-glycolic acid) (PLGA) nanoparticles.

Materials and methods: 9-Nitrocamptothecin (9-NC)-loaded PLGA nanoparticles with three different range of size (50–100?nm, 100–200?nm, 200–300?nm) were prepared by emulsion solvent-evaporation method. The pharmacokinetic study in rats of these nanoparticles with borneol was carried out.

Results: The experiments showed that the encapsulation drug in nanoparticles with size below 200?nm could improve the oral bioavailability of 9-NC. The small size nanoparticles (50–100?nm) had a better improvement efficacy. As for borneol, it played a significant promotion effect only on the small nanoparticles. Moreover, there was no significant influence on the nanoparticles with size more than 100?nm.

Discussion and conclusion: The study indicated that both entrapping drug in nanoparticles with the size below 100?nm and coadministrating with borneol could enhance the gastrointestinal absorption of water insoluble drug. The combination of the two strategies provides a potential approach to improve the oral bioavailability of drug.     

A novel intranasal breath-powered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine

Introduction: AVP-825, formerly ‘OptiNose Sumatriptan,’ is an investigational Breath-Powered^TM Bi-Directional^TM intranasal delivery system containing low-dose sumatriptan (22 mg intranasal powder) that avoids limitations of other types of intranasal administration by taking advantage of unique features of nasal anatomy and physiology.

Areas covered: This review summarizes intranasal drug delivery for migraine, how the breath-powered technology works, and AVP-825 pharmacokinetic, efficacy and safety/tolerability findings. To identify AVP-825 clinical studies, a PubMed/MEDLINE database search was conducted with the terms AVP-825, OptiNose, OptiNose Sumatriptan, Breath-Powered Nasal Delivery or sumatriptan powder. Of 20 articles, 5 clinical studies were identified, including the head-to-head comparative COMPASS trial (AVP-825 vs oral sumatriptan) and two placebo-controlled studies.

Expert opinion: AVP-825 has faster sumatriptan absorption versus oral tablets or traditional liquid nasal spray. In Phase II/III randomized, double-blind, placebo-controlled trials, AVP-825 produced early and sustained efficacy with minimal triptan-related adverse effects. In COMPASS, AVP-825 produced earlier reduction of migraine pain intensity and migraine-associated symptoms than 100 mg oral sumatriptan, and higher early rates of pain relief and pain freedom, similar sustained efficacy, and fewer atypical sensations. AVP-825 has the potential to provide migraine patients with improved intranasal administration of sumatriptan that may enhance efficacy and tolerability.     

利用计算机模拟技术对头孢克肟口服固体制剂有效性的研究与评价

目的：本研究建立了一种头孢克肟口服固体制剂通用型有效性评价方法。方法：通过对品种结构、理化性质、药代动力学特征和生物药剂学参数的研究和确证,结合静脉注射、口服等不同给药途径在比格犬及人类等不同种属中的药时曲线数据,建立并验证人口服头孢克肟的生理药代动力学模型,以此模拟口服头孢克肟在人体内的吸收、分布、代谢、消除过程,拟合药物的累计吸收曲线,作为品种口服固体制剂溶出曲线的评价依据。结果：通过对不同规格片剂、分散片、胶囊、颗粒剂和混悬剂的体内数据的验证比较,证实该模型应用的适用性和准确性。结论：本研究建立的有效性评价方法,能够明确溶出度行为与药物在体内吸收的关系,提高体外有效性评价的可靠性和准确度,可大幅度降低仿制药评价的过程成本。     

Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs

Introduction: Many amphiphilic copolymers have recently been synthesized as novel promising micellar carriers for the delivery of poorly water-soluble anticancer drugs. Studies on the formulation and oral delivery of such micelles have demonstrated their efficacy in enhancing drug uptake and absorption, and exhibit prolonged circulation time in vitro and in vivo.

Areas covered: In this review, literature on hydrophobic modifications of several hydrophilic polymers, including polyethylene glycol, chitosan, hyaluronic acid, pluronic and tocopheryl polyethylene glycol succinate, is summarized. Parameters influencing the properties of polymeric micelles for oral chemotherapy are discussed and strategies to overcome main barriers for polymeric micelles peroral absorption are proposed.

Expert opinion: During the design of polymeric micelles for peroral chemotherapy, selecting or synthesizing copolymers with good compatibility with the drug is an effective strategy to increase drug loading and encapsulation efficiency. Stability of the micelles can be improved in different ways. It is recommended to take permeability, mucoadhesion, sustained release, and P-glycoprotein inhibition into consideration during copolymer preparation or to consider adding some excipients in the formulation. Furthermore, both the copolymer structure and drug loading methods should be controlled in order to get micelles with appropriate particle size for better absorption.     

Transepithelial transport of prodrugs of the HIV protease inhibitors saquinavir,indinavir, and nelfinavir across Caco-2 cell monolayers

Purpose. This study is dedicated to the permeation of various amino acid-, D-glucose-, and PEG-conjugates of indinavir, saquinavir, and nelfinavir across monolayers of Caco-2 cells as models of the intestinal barrier. This screening is aimed at detecting the most promising prodrugs for improving the intestinal absorption of these protease inhibitors. Methods. The bidirectional transport of the prodrugs was investigated using P-gp-expressing Caco-2 monolayers grown on membrane inserts using high-performance liquid chromatography for quantitation. Results. The L-valyl, L-leucyl, and L-phenylalanyl ester conjugates led to an enhancement of the absorptive flux of indinavir or saquinavir. These results are likely attributable to an active transport mechanism and/or to a decrease of their efflux by carriers such as P-gp. Connection of tyrosine through its hydroxyl, of D-glucose, or of polyethylene glycol decreased their absorptive and secretory diffusion. Conclusions. Conjugation of the protease inhibitors to amino acids constitutes a most appealing alternative that could improve their intestinal absorption and oral bioavailability. Whether it could improve their delivery into the central nervous system remains to be explored. D-Glucose conjugation will most probably not improve their intestinal absorption or their crossing of the blood-brain barrier. If some pharmacologic benefits are to be expected from PEG-protease inhibitor conjugates, they must then be administered intravenously.     

Drug delivery/imaging multifunctionality of mesoporous silica-based composite nanostructures

Introduction: Biocompatible mesoporous silica nanoparticles (MSNs) are regarded as one of the most promising inorganic drug delivery systems (DDSs) to concurrently enhance the therapeutic efficiency and mitigate the side effects of anticancer drugs. Elaborately combining multicomponents with MSNs will endow them with specific functionalities for cancer therapy and diagnosis, such as targeted drug delivery, intelligent on-demand drug releasing, synergistic therapy, diagnostic imaging and so on.

Areas covered: This review discusses the state-of-the-art potential obstacles and further perspectives of the chemical design/synthesis, in vitro/in vivo pharmaceutical evaluations and potential clinical translations of multifunctional mesoporous silica-based nanomaterials for biotechnological and biomedical applications, especially against cancer. These topics cover the years from 2001 to 2013.

Expert opinion: Through the comprehensive evaluations of the biosafety and pharmaceutical efficiency, elaborately designed/fabricated mesoporous silica-based composite nanoparticles show great potentials in clinical applications for efficient diagnostic imaging and chemotherapy of cancer.     

Lipid Microemulsions for Improving Drug Dissolution and Oral Absorption: Physical and Biopharmaceutical Aspects

Purpose. This review highlights the state-of-the-art in pharmaceutical microemulsions with emphasis on self-emulsifying systems, from both a physical and biopharmaceutical perspective. Although these systems have several pharmaceutical applications, this review is primarily focused on their potential for oral drug delivery and intestinal absorption improvement. Methods. Physicochemical characteristics and formulation design based on drug solubility and membrane permeability are discussed. Results. Case studies in which lipid microemulsions have successfully been used to improve drug solubilization/dissolution and/or intestinal absorption of poorly absorbed drugs/peptides are presented. Conclusions. Drug development issues such as commercial viability, mechanisms involved, range of applicability, safety, scale-up and manufacture are outlined, and future research and development efforts to address these issues are discussed.     

Orally active-targeted drug delivery systems for proteins and peptides

Introduction: In the past decade, extensive efforts have been devoted to designing ‘active targeted’ drug delivery systems (ATDDS) to improve oral absorption of proteins and peptides. Such ATDDS enhance cellular internalization and permeability of proteins and peptides via molecular recognition processes such as ligand–receptor or antigen?antibody interaction, and thus enhance drug absorption.

Areas covered: This review focuses on recent advances with orally ATDDS, including ligand–protein conjugates, recombinant ligand–protein fusion proteins and ligand-modified carriers. In addition to traditional intestinal active transport systems of substrates and their corresponding receptors, transporters and carriers, new targets such as intercellular adhesion molecule-1 and β-integrin are also discussed.

Expert opinion: ATDDS can improve oral absorption of proteins and peptides. However, currently, no clinical studies on ATDDS for proteins and peptides are underway, perhaps due to the complexity and limited knowledge of transport mechanisms. Therefore, more research is warranted to optimize ATDDS efficiency.     

Physical methods to promote drug delivery on mucosal tissues of the oral cavity

Introduction: The success of drug delivery through the mucosal tissue of the oral cavity represents a current challenge as well as a great future perspective. The need for more rapid onset of action and improved absorption of medications has resulted in great development of drug delivery technologies that use physical methods to overcome the barrier properties of oral mucosae.

Areas covered: This review discusses the various physical techniques which have been, and are being, explored to sustain drug delivery in the oral cavity. In particular, supersaturation, eutectic formation, iontophoresis, electroporation, sonophoresis, laser radiation, photomechanical waves and needleless injection are considered. Following a careful selection of the most appropriate site and technique, in agreement with local variations of the oral mucosal permeability features, physical methods to promote drug delivery can improve treatment of diseases.

Expert opinion: Although physical methods are very promising to promote drug delivery through keratinized epithelial tissues, they are not extensively used on the oral cavity mucosae. The authors feel that, in the near future, these methods could be further developed to provide noninvasive and convenient means for locoregional/systemic delivery of drugs with poor bioavailability profile, short half-life and multiple doses scheduling. This review will help the readers in the selection of a suitable physical method for improving drug delivery in the oral cavity for future chances. The authors imagine that new formulations or devices will be marketed in the coming years.     

Microsponges: a futuristic approach for oral drug delivery

Introduction: Microparticulate drug delivery systems have, due to their advantages, guided researchers across the globe to explore them as drug carriers. This has, sequentially, led to the development of microsponges in 1988. These porous microspheres were exclusively designed for chronotherapeutic topical drug delivery but attempts to utilize them for oral, pulmonary and parenteral drug delivery were also made. Researchers have extensively studied their properties and characteristics affecting the drug release and loading. Various advances were made with this carrier particle resulting in the development of various novel development techniques and carrier particles.

Areas covered: This review deals with the considerations of the drug material to be entrapped in microsponges, pharmaceutical considerations for fabrication of microsponges, their potential for oral drug delivery, clinical perspectives and also provides an insight on the recent advances made in this field and future prospect.

Expert opinion: Clinical studies show that these carriers can increase drug efficacy. Due to their potential advantages over other carrier particles, microsponges form a prospective platform for the oral delivery of pharmaceuticals and biopharmaceuticals. Although these carriers have several advantages, they too possess some drawbacks which limit their commercialization for oral application.     

Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis

Introduction: Angiogenesis is essential to human biology and of great clinical significance. Excessive or reduced angiogenesis can result in, or exacerbate, several disease states, including tumor formation, exudative age-related macular degeneration (AMD) and ischemia. Innovative drug delivery systems can increase the effectiveness of therapies used to treat angiogenesis-related diseases.

Areas covered: This paper reviews the basic biology of angiogenesis, including current knowledge about its disruption in diseases, with the focus on cancer and AMD. Anti- and proangiogenic drugs available for clinical use or in development are also discussed, as well as experimental drug delivery systems that can potentially improve these therapies to enhance or reduce angiogenesis in a more controlled manner.

Expert opinion: Laboratory and clinical results have shown pro- or antiangiogenic drug delivery strategies to be effective in drastically slowing disease progression. Further research in this area will increase the efficacy, specificity and duration of these therapies. Future directions with composite drug delivery systems may make possible targeting of multiple factors for synergistic effects.