New delivery strategies for the old pentavalent antimonial drugs

Importance of the field: Pentavalent antimonials are the first-line drugs for treatment of the major tropical disease leishmaniasis. However, their use is limited by the need for daily parenteral administration, their severe side effects and treatment failures. As leishmaniasis belongs to the group of neglected diseases, the improvement of old drugs through new delivery approaches has more support than the development of new chemical entities.

Areas covered in this review: The review covers, from 1977 to the present, the progress achieved towards pharmaceutically acceptable liposome-based formulations of antimonials, identification of specific ligands for improved targeting of infected macrophages and new approaches for oral and topical delivery of antimonial drugs.

What the reader will gain: Insights into the most promising delivery strategies to improve antimonial therapy and the chemical basis and future directions for achieving innovative orally and topically effective formulations.

Take home message: The development of drug delivery strategies for the old pentavalent antimonials is a still growing and promising field, with expected innovations in the near future from improved knowledge of antimony chemistry.     

Liposomes for targeted delivery of antithrombotic drugs

Background: Targeted delivery of antithrombotic (thrombolytic) drugs is expected to increase their efficacy and decrease side effects, especially in the case of thrombolytic enzymes. Liposomes, phospholipid nanosized bubbles with a bilayered membrane structure, have drawn a lot of interest as pharmaceutical carriers for drugs and genes. In particular, several attempts have been made to use liposomes as vehicles for antithrombotic agents. Objective: This review analyzes the available data on the application of liposomes, including liposomes targeted by specific ligands, for the delivery of antithrombotic/thrombolytic agents in order to increase their efficacy and decrease side effects. Methods: The papers published on the subject of liposomes loaded with antithrombotic agents, mainly over the last 10 – 15 years, will be discussed. Conclusion: Liposomes loaded with various antithrombotic drugs, though they have been the subject of a significant number of experimental papers, can hardly be considered as real candidates for clinical application in the near future.     

PHEA-graft-polybutylmethacrylate copolymer microparticles for delivery of hydrophobic drugs

Polymeric microparticles encapsulating two model hydrophobic drugs, beclomethasone dipropionate (BDP) and flutamide (FLU) were prepared by using the high pressure homogenization-solvent evaporation method starting from a oil-in-water emulsion. For the preparation of polymeric microparticles a α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) graft copolymer with comb like structure was properly synthesized via grafting from atom transfer radical polymerization (ATRP) technique, by using two subsequent synthetic steps. In the first step a polymeric multifunctional macroinitiator was obtained by the conjugation of a proper number of 2-bromoisobutyryl bromide (BIB) residues to the PHEA side chains, obtaining the PHEA-BIB copolymer. PHEA-BIB copolymer was then used as macroinitiator for the polymerization via ATRP of the hydrophobic monomer such as butyl methacrylate (BMA) to obtain the α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide-co-(N-2-ethylen-isobutyrate)-graft-poly(butyl methacrylate) copolymer (PHEA-IB-p(BMA)). Spherical microparticles with 1-3 microns diameter were prepared. Microparticles loaded with BDP or FLU were also prepared. In vitro mucoadhesion and enzymatic degradation studies evidenced bioadhesive properties and biodegradability of prepared microparticles, while release studies showed a different release profiles for the two loaded drugs: BDP was totally released from nanoparticles until 24h in pulmonary mimicking conditions; differently a slower FLU release rate was observed in gastro-intestinal mimicking conditions. The in vitro cytotoxicity activity was assessed using 16HBE and Caco-2 cell lines. Results showed that exposure of both cell lines to BDP-loaded microparticles do not inhibited the cell growth; on the contrary FLU-loaded microparticles inhibited the cell growth, in particular of the Caco-2 cancer cell line, in a concentration- and time-dependent manner. Finally, uptake studies demonstrated that BDP-loaded microparticles and FLU-loaded microparticles effectively increased uptake of loaded drugs in a time-dependent manner, respectively on 16HBE and Caco-2 cell lines.     

Bile salts-containing vesicles: promising pharmaceutical carriers for oral delivery of poorly water-soluble drugs and peptide/protein-based therapeutics or vaccines

Abstract

Most of the new drugs, biological therapeutics (proteins/peptides) and vaccines have poor performance after oral administration due to poor solubility or degradation in the gastrointestinal tract (GIT). Though, vesicular carriers exemplified by liposomes or niosomes can protect the entrapped agent to a certain extent from degradation. Nevertheless, the harsh GIT environment exemplified by low pH, presence of bile salts and enzymes limits their capabilities by destabilizing them. In response to that, more resistant bile salts-containing vesicles (BS-vesicles) were developed by inclusion of bile salts into lipid bilayers constructs. The effectiveness of orally administrated BS-vesicles in improving the performance of vesicles has been demonstrated in researches. Yet, these attempts did not gain considerable attention. This is the first review that provides a comprehensive overview of utilizing BS-vesicles as a promising pharmaceutical carrier with a special focus on their successful applications in oral delivery of therapeutic macromolecules and vaccines. Insights on the possible mechanisms by which BS-vesicles improve the oral bioavailability of the encapsulated drug or immunological response of entrapped vaccine are explained. In addition, methods adopted to prepare and characterize BS-vesicles are described. Finally, the gap in the scientific researches tackling BS-vesicles that needs to be addressed is highlighted.     

Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs

Introduction: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently.

Areas covered: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials.

Expert opinion: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic.     

Hydrogels with smart systems for delivery of hydrophobic drugs

Introduction: Smart hydrogel systems present opportunities to not only provide hydrophobic molecule encapsulation capability but to also respond to specific delivery routes.

Areas covered: An overview of the design principles, preparation methods and applications of hydrogel systems for delivery of hydrophobic drugs is given. It begins with a summary of the advantages of hydrogels as delivery vehicles over other approaches, particularly macromolecular nanocarriers, before proceeding to address the design and preparation strategies and chemistry involved, with a particular focus on the introduction of hydrophobic domains into (naturally) hydrophilic hydrogels. Finally, the applications in different delivery routes are discussed.

Expert opinion: Modifications to conventional hydrogels can endow them with the capability to carry hydrophobic drugs but other functions as well, such as the improved mechanical stability, which is important for long-term in vivo residence and/or self-healing properties useful for injectable delivery pathways. These modifications harness hydrophobic-hydrophobic forces, physical interactions and inclusion complexes. The lack of in-depth understanding of these interactions, currently limits more delicate and application-oriented designs. Increased efforts are needed in (i) understanding the interplay of gel formation and simultaneous drug loading; (ii) improving hydrogel systems with respect to their biosafety; and (iii) control over release mechanism and profile.     

Entrapment of Cyclodextrin-Drug Complexes into Liposomes: Potential Advantages in Drug Delivery

Abstract

A novel concept in drug delivery discussed here, takes advantage of certain properties of the drug “containers” cyclodextrins and liposomes to combine them into a single system thus circumventing problems associated with both systems. The concept, entailing entrapment of water-soluble cyclodextrin-drug inclusion complexes in liposomes, would allow accommodation of insoluble drugs in the aqueous phase of vesicles. This would potentially increase the drug to lipid mass ratio to levels above those attained by conventional drug incorporation into the lipid phase, enlarge the range of insoluble drugs amenable to encapsulation to include, for instance, membrane destabilizing agents, allow targeting of complexes to specific sites and reduce toxicity. In the present work, soluble inclusion complexes of hydroxypropyl-β-cyclodextrin with dehydroepiandrosterone, retinol and retinoic acid were prepared and entrapped into mutlilamellar liposomes by the dehydration-rehydration procedure. Complex-containing liposomes were then exposed to blood plasma. Results show that complex entrapment into liposomes depends on the lipid composition used. Nearly all of the cyclodextrin and considerable portions of the drugs were found to remain associated with the carrier in the presence of plasma.     

Liposomes: a promising carrier for respiratory syncytial virus therapeutics

ABSTRACT

Introduction: Human respiratory syncytial virus (RSV) is a common respiratory virus that causes severe lower respiratory tract infection in infants, children and aged adults. Currently, there is no active prophylaxis present in the market for RSV infection; however, there are over a dozen compounds being tested in the laboratory as well as clinical trials. To increase the efficiency and safety of these therapeutics, there is a need for delivery vehicles.

Areas covered: Liposomes can be used for delivering anti-RSV agents with the advantage of modulating and eliciting the desired adjuvant effect by the different combination of lipids. This review discusses the promising application of liposome for anti-RSV therapeutics.

Expert opinion: Liposomes are attracting attention for delivery of pulmonary therapeutics, since they offer compatibility for delivering drugs, vaccines and other therapeutic molecules. Variation in liposome size and composition gives flexibility for the amount and number of deliverables, whilst targeted delivery with the capability for immunomodulation makes liposomes a promising candidate for RSV therapeutic applications.     

Drug delivery strategies for poorly water-soluble drugs: the industrial perspective

Introduction: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation.

Areas covered: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes. In addition, the use of biorelevant dissolution media to assess dissolution and solubility properties is described. Suggestions are also included to systematically address development hurdles typical of poorly water-soluble compounds intended for parenteral or oral administration.

Expert opinion: A holistic assessment is recommended to select the appropriate delivery technology by taking into account technical as well as intellectual property considerations. Therefore, first and foremost, a comprehensive physico-chemical characterization of poorly water-soluble compounds can provide the key for a successful selection and development outcome. In this context, the identified physical form of the compound in the formulation is used as a guide for a risk–benefit assessment of the selected oral delivery technology. The potential of nano-suspensions for intravenous administration is unclear. In the case of oral administration, nano-suspensions are mainly used to improve the oral absorption characteristics of micronized formulations. The development of an in situ instantaneous solubilization method, based on stable, standardized liposomes with low toxicity, opens new avenues to solubilize poorly water-soluble compounds.     

Evaluation of hydrophobic nanoparticulate delivery system for insulin

Insulin loaded hydrophobic nanoparticles were prepared by solvent diffusion followed by lyophilization. Nanoparticles were characterized for mean size by dynamic laser scattering and for shape by scanning electron microscopy. Insulin encapsulation efficiency, in vitro stability of nanoparticles in presence of proteolytic enzymes and in vitro release were determined by high pressure liquid chromatography analysis. The biological activity insulin from the nanopraticles was estimated by enzyme-linked immunosorbant assay and in vivo using Wister diabetic rats. Nanoparticles ranged 0.526±0.071 μm in diameter. Insulin encapsulation efficiency was 95.7±1.2%. Insulin hydrophobic nanoparticles suppressed insulin release promoted sustained release in pH 7.4 phosphate buffer and shown to protect insulin from enzymatic degradation in vitro in presence of chymotripsin. Nanoencapsulated insulin was bioactive, demonstrated through both in vivo and in vitro.     

多胺胆固醇缀合物纳米粒作为反义核苷酸传递系统的研究

目的研究多胺胆固醇缀合物传递反义核苷酸的能力。方法通过对自制脂质体的载药量、红细胞毒性、M3骨髓瘤细胞的转染实验。结果自制脂质体具有比常规脂质体良好的载药量,并且对红细胞毒性相对偏小,对M3骨髓瘤细胞具有一定的转染能力。结论自制的脂质体具有一定的应用前景。     

与环糊精共价结合的前药在结肠靶向释药系统中的研究进展

综述了几种与环糊精共价键合的前药的释药行为和机理,并阐述了其在结肠靶向释药系统中的研究进展.     

Homogeneous PLGA-lipid nanoparticle as a promising oral vaccine delivery system for ovalbumin

In this study, a polymeric lipid nanoparticle (NP) (simplified as Lipid NP) was reported as a promising oral vaccine delivery system. The Lipid NPs composed of a hydrophobic polymeric poly(d,l-lactide-co-glycolide) (PLGA) core and a surface coating of lipid monolayer. Membrane emulsification technique was used to obtain uniform-sized Lipid NPs. Ovalbumin (OVA) was used as a model vaccine. Compared with the pure PLGA NPs, the Lipid NPs achieved higher loading capacity (LC) and entrapment efficiency (EE) for the encapsulated OVA. An in vitro oral release profile showed that the OVA-Lipid NPs were with lower initial burst and could protect the loaded OVA from the harsh gastrointestinal (GI) environment for a long time. In addition, a human microfold cell (M-cell) transcytotic assay demonstrated that due to a lipid layer structure on the particle surface, the Lipid NPs showed higher affinity to the M-cells. Since the M-cell in the intestinal epithelium played an important role in particle transportation as well as intimately associated with the underlying immune cells, the OVA-Lipid NPs effectively induced mucosal and humoral immune responses.     

Nebulizer-compatible liquid formulations for aerosol pulmonary delivery of hydrophobic drugs: glucocorticoids and cyclosporine

This review discusses pulmonary delivery of glucocorticoids and cyclosporine in pharmaceutically acceptable organic solvents and liposomes, as well as in micellar solutions and microemulsions, by means of liquid aerosols generated by nebulizers. The review points out the importance of a variety of parameters for successful treatment of immunologically mediated lung diseases by inhalation of drug containing aerosols with particular references to physico-chemical properties of formulations, aerosol parameters, pharmacokinetics, and lung deposition in experimental animals and humans. The prospects for the use of these types of formulations for clinical treatment of asthma, lung transplant rejection processes and other lung diseases are summarized.     

Nanosuspensions: a promising drug delivery strategy

Nanosuspensions have emerged as a promising strategy for the efficient delivery of hydrophobic drugs because of their versatile features and unique advantages. Techniques such as media milling and high-pressure homogenization have been used commercially for producing nanosuspensions. Recently, the engineering of nanosuspensions employing emulsions and microemulsions as templates has been addressed in the literature. The unique features of nanosuspensions have enabled their use in various dosage forms, including specialized delivery systems such as mucoadhesive hydrogels. Rapid strides have been made in the delivery of nanosuspensions by parenteral, peroral, ocular and pulmonary routes. Currently, efforts are being directed to extending their applications in site-specific drug delivery.     

Targeted treatment for osteoarthritis: drugs and delivery system

The management of osteoarthritis (OA) is a clinical challenge due to the particular avascular, dense, and occluded tissue structure. Despite numerous clinical reports and animal studies, the pathogenesis and progression of OA are still not fully understood. On the basis of traditional drugs, a large number of new drugs have been continuously developed. Intra-articular (IA) administration for OA hastens the development of targeted drug delivery systems (DDS). OA drugs modification and the synthesis of bioadaptive carriers contribute to a qualitative leap in the efficacy of IA treatment. Nanoparticles (NPs) are demonstrated credible improvement of drug penetration and retention in OA. Targeted nanomaterial delivery systems show the prominent biocompatibility and drug loading-release ability. This article reviews different drugs and nanomaterial delivery systems for IA treatment of OA, in an attempt to resolve the inconsonance between in vitro and in vivo release, and explore more interactions between drugs and nanocarriers, so as to open up new horizons for the treatment of OA.     

A lipid-based delivery system for antisense oligonucleotides derived from a hydrophobic complex

Antisense oligodeoxynucleotides (ASOs) prevent expression of proteins by binding to specific regions of mRNA. This report investigates a potential lipid-based delivery system for ASO. A hydrophobic complex was recovered following addition of cationic lipids to ASOs in a Bligh and Dyer monophase [chloroform/methanol/water (1:2.1:1, v/v/v)]. The addition of monovalent cationic lipids (dioleyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dioleoyltrimethylammonium propane), resulted in > 95% recovery of the ASOs from the organic phase when ASO phosphate charge was neutralized. Cholesteryldimethylaminoethylcarbamate mediated efficient extraction at a charge ratio (+/-) > 5.2. ASOs could not be extracted into the organic phase by the polyvalent lipids, dioctadecylamidoglycyl spermine and 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propaminium trifluoroacetate, even at a charge ratio (+/-) > 5. Dioleoylphosphatidylethanolamine, but not dioleoylphosphatidylcholine, prevented formation and destabilized the hydrophobic complexes. The characterization of the hydrophobic complex led to the development of lipid-ASO particles containing dioleyldimethylammonium chloride, dioleoylphosphatidylethanolamine and poly(ethylene glycol)-conjugated phosphatidylethanolamine (LAPs). When FITC-labeled ASOs in LAPs were added to B-cell lymphoma cells (DoHH2) in vitro, cell-associated ASO decreased as poly(ethylene glycol)-conjugated phosphatidylethanolamine incorporation increased. Western Blot analysis demonstrated that no significant downregulation of Bcl-2 protein was observed when using LAPs. The results suggest that the use of stabilized PEG-conjugated lipids may be detrimental for cationic lipid-based ASO delivery.