Improving drug solubility for oral delivery using solid dispersions.

The solubility behaviour of drugs remains one of the most challenging aspects in formulation development. With the advent of combinatorial chemistry and high throughput screening, the number of poorly water soluble compounds has dramatically increased. Although solid solutions have tremendous potential for improving drug solubility, 40 years of research have resulted in only a few marketed products using this approach. With the introduction of new manufacturing technologies such as hot melt extrusion, it should be possible to overcome problems in scale-up and for this reason solid solutions are enjoying a renaissance. This article begins with an overview of the historical background and definitions of the various systems including eutectic mixtures, solid dispersions and solid solutions. The remainder of the article is devoted to the production, the different carriers and the methods used for the characterization of solid dispersions.     

Polymeric nanoparticle drug delivery technologies for oral delivery applications

Introduction: Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles (NPs) are one technology being developed to enable clinically feasible oral delivery.

Areas covered: This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal (GI) barriers using polymeric NPs will be considered, including mucoadhesive biomaterials and targeting of NPs to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations.

Expert opinion: There have been many approaches used to overcome the transport barriers presented by the GI tract, but most have been limited by low bioavailability. Recent strategies targeting NPs to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and NPs across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric NP technologies and enable the translation of these technologies to clinical practice.     

Therapeutic applications of hydrogels in oral drug delivery

Introduction: Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

Areas covered: This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Expert opinion: Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.     

Transdermal drug delivery: problems and possibilities

Transdermal drug delivery has, in recent years, attracted considerable interest. However, despite the obvious advantages of this novel route of drug administration to achieve systemic therapeutic effect, there remain important, and sometimes severe, limitations on the physiochemical and pharmacological properties of the agent to be delivered. This article reviews the present status and accomplishments of transdermal drug delivery. The benefits, disadvantages, and, as yet, unresolved problems inherent to drug input via the skin are addressed. Deficiencies in our knowledge of the percutaneous absorption process in man are identified, and approaches to elucidate these unknowns are discussed. Finally, with respect to the future potential of transdermal drug delivery, experimental and modeling techniques, which can be employed to assess the feasibility and promise of a therapeutic candidate, are described and illustrated with pertinent examples.     

Supersaturation and crystallization: non-equilibrium dynamics of amorphous solid dispersions for oral drug delivery

Introduction: Amorphous solid dispersions (ASDs) are one of the key formulation technologies that aid the development of poorly soluble candidates. However, their dynamic behaviors, including dissolution and crystallization processes, are still full of mystery. Further understanding of these processes should enhance their wider use.

Areas covered: The first part of this review describes the current understanding of the dissolution of ASDs, where phase separation behavior is frequently involved and attempts to develop appropriate dissolution tests to achieve an in vitro–in vivo correlation are examined. The second part of this review discusses crystallization of the drug molecule with the eventual aim of establishing an accelerated testing protocol for predicting its physical stability.

Expert opinion: The phase separation behavior from the supersaturated state during the dissolution test must be understood, and its relevance to the oral absorption behavior needs to be clarified. Research efforts should focus on the differences between the phase behavior in in vitro and in vivo situations. Initiation time of the crystallization was shown to be predicted only from storage and glass transition temperatures. This finding should encourage the establishment of testing protocol of the physical stability of ASDs.     

Liposomes for drug delivery: developments and possibilities

The ability to target a drug specifically to its site of action has long been a goal in therapeuties. Liposomes (phospholipid vesicles) have been investigated as a means of achieving such selectivity and of prolonging the duration of drug activity. With reference to current and future clinical applications, this article outlines why liposomes are appropriate vehicles for drug delivery and describes the possible further development of liposome-based pharmaceutical formulations.     

Nano-encapsulation of azole antifungals: potential applications to improve oral drug delivery

The present study was designed to improve the oral bioavailability of two clinically important antifungal drugs-clotrimazole and econazole. Each drug was encapsulated in nanoparticles of a synthetic polymer (polylactide-co-glycolide, PLG) or a natural polymer (alginate stabilized with chitosan). The nanoparticles were prepared by the emulsion-solvent-evaporation technique in case of PLG and by the cation-induced controlled gelification in case of alginate. Drug encapsulation efficiency was better (>90%) for the alginate formulation compared with the PLG formulation (nearly 50%). The formulations were orally administered to mice and the drugs were analyzed in plasma by a validated HPLC technique. The biodistribution/pharmacokinetic data suggested that there was a controlled drug release for 5-6 days with each of the formulations, compared with unencapsulated drugs, which were cleared within 3-4 h of oral/intravenous administration. There was a striking improvement in the relative and absolute bioavailability of each drug. Further, the drugs were detected in the tissues (lungs, liver and spleen) till 6-8 days in case of nanoparticles whereas free drugs were cleared by 12 h. Overall, the alginate formulation appeared to be better than the PLG formulation. The results emphasize the power of nanotechnology to make the concept of enhancement in oral bioavailability of azole antifungal drugs come to reality.     

Solid colloidal drug delivery systems: Nanoparticles

After outlining the criteria of an ideal solid colloidal drug delivery system, a review is made under 5 headings of the various systems described in the literature. None of these systems are ideal. The problems of maximizing the drug content of the solid system are discussed. Viruses and vaccines, diagnostic agents, cytotoxics, flukicides and antiarthritics are given as examples of the drugs that may be incorporated into these so-called nanoparticles. The biggest barrier to successful exploitation of nanoparticles to minimize rapid hepatic clearance.     

Nanotopography applications in drug delivery

Refinement of micro- and nanofabrication in the semiconductor field has led to innovations in biomedical technologies. Nanotopography, in particular, shows great potential in facilitating drug delivery. The flexibility of fabrication techniques has created a diverse array of topographies that have been developed for drug delivery applications. Nanowires and nanostraws deliver drug cytosolically for in vitro and ex vivo applications. In vivo drug delivery is limited by the barrier function of the epithelium. Nanowires on microspheres increase adhesion and residence time for oral drug delivery, while also increasing permeability of the epithelium. Low aspect ratio nanocolumns increase paracellular permeability, and in conjunction with microneedles increase transdermal drug delivery of biologics in vivo. In summary, nanotopography is a versatile tool for drug delivery. It can deliver directly to cells or be used for in vivo delivery across epithelial barriers. This editorial highlights the application of nanotopography in the field of drug delivery.     

Ultrasound-induced cavitation: applications in drug and gene delivery

Ultrasound, which has been conventionally used for diagnostics until recently, is now being extensively used for drug and gene delivery. This transformation has come about primarily due to ultrasound-mediated acoustic cavitation - particularly transient cavitation. Acoustic cavitation has been used to facilitate the delivery of small molecules, as well as macromolecules, including proteins and DNA. Controlled generation of cavitation has also been used for targeting drugs to diseased tissues, including skin, brain, eyes and endothelium. Ultrasound has also been employed for the treatment of several diseases, including thromboembolism, arteriosclerosis and cancer. This review provides a detailed account of mechanisms, current status and future prospects of ultrasonic cavitation in drug and gene delivery applications.     

Solid lipid nanoparticles incorporated in dextran hydrogels: a new drug delivery system for oral formulations

Solid lipid nanoparticles (SLN) containing or not (S)-(+)-2-(4-isobutylphenyl)propionic acid (ibuprofen) were prepared with Preciol ATO 5 as lipid phase by the hot homogenization technique and characterized through particle size analyses and zeta potential measurements. DSC experiments carried out on the freeze-dried samples of loaded SLN showed a shift of the melting endotherm of the lipid phase, with the maximum at a temperature value higher then that of the "empty" SLN. (1)H NMR of the nanosuspension allowed to calculate the encapsulation efficiency of the particles that was 52+/-3%. By adding dextran methacrylate (DEX-MA) to the aqueous phase and submitting the mixture to UV irradiation, systems of SLN (drug-loaded and unloaded) incorporated into a dextran hydrogel were prepared. Finally, dissolution studies of ibuprofen from the freeze-dried samples were performed. The comparison among the release profiles of ibuprofen from SLN, DEX-MA hydrogel and SLN/DEX-MA-hydrogel allows to affirm that this last system, retaining about 60% of the drug after 2h in acid medium and releasing it slowly in neutral solution, is suitable for modified delivery oral formulations.     

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.     

Solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of glimepiride: development and antidiabetic activity in albino rabbits

Abstract

Context: This study presents novel self-nanoemulsifying drug delivery system potential of oral delivering which leads poorly aqueous soluble drug glimepiride.

Objective: The objective of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) for the improved oral delivery of glimepiride and to evaluate its therapeutic efficacy in albino rabbits.

Results and discussion: The droplet size analyses revealed a droplet size of less than 200?nm. The solid state characterization of S-SNEDDS by scanning electron microscopy (SEM), X-ray powder diffraction and differential scanning calorimetry (DSC) revealed the absence of crystalline glimepiride in the S-SNEDDS. The in vitro dissolution studies revealed that the significant improvement in glimepiride release characteristics. The effect of S-SNEDDS on therapeutic efficacy of glimepride was assessed in albino rabbits by monitoring blood glucose levels and compared with free drug suspension, L-SNEDDS. The S-SNEDDS showed significant (p?<?0.05) increase in in vitro drug release and therapeutic efficacy as compared with free drug.

Conclusion: This study demonstrated that S-SNEDDS is a promising novel drug delivery system of glimepride to enhance oral delivery.     

Fluorescence imaging: applications in drug delivery research

In the context of drug delivery it is crucial to gain knowledge of nature of the cell's internal barriers, as well as one needs to be aware of requirements for the study of spatial and temporal interactions of drug delivery vehicles with the cell. Fluorescent imaging technology can be a great innovation in the field of science as far as study of live cell imaging and dynamic events are concerned. The technique has also demonstrated the ability to integrate the anatomic, functional, and statistical data. The current review article discusses various fluorescent techniques and also elaborates the scope of fluorescent imaging in the field of drug delivery.     

Dendritic systems in drug delivery applications

The design of well-defined particulate carrier systems with controlled size, shapes and physicochemical characteristics is becoming a focal point in the field of biomedicine and drug delivery. Dendrimers are one of the emerging technologies of recent times and have served as a unique platform to achieve the development as novel drug delivery scaffolds. Dendrimers may be engineered to meet the specific needs of biologically active agents, which can either be encapsulated within dendrimers or chemically attached to these units. The large number of active functional groups on the surface of dendrimers allows them to be meticulously tailored and to act as nano-scaffolds or nano-containers of various categories of drugs. The architecture of modified dendrimers has posed a challenge to drug delivery, in particular with respect to their in vivo metabolic fate. The drug delivery applications of dendrimers presented in this article provide an insight of their potential and substantiate the major roles for the future of these nanoconstructs.     

Silica materials in drug delivery applications

In this review article we collect and analyse preparation, chemistry and properties of silica materials relevant for drug delivery applications. We review some of the most relevant milestones in the research of silica materials for implantable, oral, intravenous and dermal drug delivery systems. Preparation, chemistry and drug delivery characteristics of fumed silica nanoparticles (oral and dermal delivery route), silica xerogels (implant delivery), mesoporous silica materials (implant and oral delivery) and mesoporous silica spheres (intravenous delivery) with particular emphasis on their role in anticancer therapy and the design of stimuli responsive drug delivery systems are analysed. Recent progress in the research of silica materials for controlled drug delivery, namely, biocompatibility aspects, research on hybrid materials, anticancer and stimuli-responsive mesoporous silica materials are particularly emphasized.     

Dendritic systems in drug delivery applications

The design of well-defined particulate carrier systems with controlled size, shapes and physicochemical characteristics is becoming a focal point in the field of biomedicine and drug delivery. Dendrimers are one of the emerging technologies of recent times and have served as a unique platform to achieve the development as novel drug delivery scaffolds. Dendrimers may be engineered to meet the specific needs of biologically active agents, which can either be encapsulated within dendrimers or chemically attached to these units. The large number of active functional groups on the surface of dendrimers allows them to be meticulously tailored and to act as nano-scaffolds or nano-containers of various categories of drugs. The architecture of modified dendrimers has posed a challenge to drug delivery, in particular with respect to their in vivo metabolic fate. The drug delivery applications of dendrimers presented in this article provide an insight of their potential and substantiate the major roles for the future of these nanoconstructs.     

Mesoporous silicon in drug delivery applications

During the last few years, a number of interesting drug delivery applications of mesoporous materials have been demonstrated. Mesoporous silicon has many important properties advantageous to drug delivery applications. The small size of the pores confines the space of a drug and engages the effects of surface interactions of the drug molecules and the pore wall. The size of the pores and the surface chemistry of the pore walls may be easily changed and controlled. Depending on the size and the surface chemistry of the pores, increased or sustained release of the loaded drug can be obtained. Drug loading from a solution at room temperature enables the use of porous silicon (PSi) also with sensitive therapeutic compounds susceptible to degradation, like peptides and proteins. This article reviews the fabrication and chemical modifications of PSi for biomedical applications, and also the potential advantages of PSi in drug delivery.