Delivery of amitriptyline by intravenous and intraperitoneal administration compared in the same animal by whole-body mass spectrometry imaging of a stable isotope labelled drug substance in mice

ABSTRACT

Background: The distribution and metabolism of a drug in the organism are dependent on the administration route as well as on the drug formulation. It is important to be able to assess which impact the administration route or formulation of a drug has for its distribution and metabolism.

Methods: The antidepressant drug amitriptyline was intravenously (IV) dosed to a mouse and immediately after, a similar amount of a deuterium-labeled version of the drug was intraperitoneally (IP) dosed to the same animal. Whole-body cryo-sections were made at t = 5, 15, 30, and 60 min post-dosing, and the two drug substances and metabolites were imaged by DESI-MS/MS.

Results: After 5 min, the IV dosed drug was detected throughout the animal, while the IP dosed drug was primarily found in the abdominal cavity. At later times, the differences between the two administration routes became less pronounced. Two administration routes provided highly similar metabolite distributions, also at early time points.

Conclusion: The method provides a unique way to compare delivery and metabolism of a drug by different administration routes or formulations in the very same animal, eliminating uncertainties caused by animal-to-animal variation and avoiding the use of radioactive labeling.     

Exploitation of lipid-polymeric matrices at nanoscale for drug delivery applications

ABSTRACT

Introduction: Progress in drug delivery and a better quality of life for patients, relies on the development of new and suitable drug carrier systems, with unequivocal therapeutic benefits, low systemic toxicity and reduced side effects. Lipid-polymeric nanoparticles have been explored to produce nanocarriers due to their features and applications such as high drug entrapment, physical-chemical stability and controlled release properties.

Areas covered: In this review, we describe several hybrid nanoparticles obtained from mixing a polymer with a lipid matrix. This association can potentiate the efficacy of drug delivery systems, due to the enhancement of encapsulation efficiency and loading capacity, tailoring the drug release according to the therapeutic purpose, and improving the drug uptake by targeting it to specific receptors. Contrary to lipid nanoparticles, these hybrid nanoparticles can decrease the initial burst release and promote a more sustained and localized release of the drug.

Expert Opinion: Lipid-polymeric nanoparticles are versatile vehicles for drug delivery by different administration routes in the treatment of multiple diseases. Different solid lipids, polymers, surfactants and techniques for producing these carriers have been investigated, revealing the importance of their composition to achieve optimal characteristics to drug delivery.     

Polymer-drug conjugates: recent progress on administration routes

Introduction: Polymer-drug conjugates are an important part of polymer therapeutics. Recently, they have been used as an appealing platform for drug delivery. As a delivery vector, the route of administration performs a serious impact on the accessibility of drug molecules to their respective target site and therapeutic index. Furthermore, the physicochemical and biological properties of conjugates also correlate distinctly with the route of administration.

Areas covered: This article reviews the recent advances of polymer-drug conjugates as drug delivery systems through parenteral, enteral and topical routes. In particular, it mainly focuses on the classical and emerging routes such as injection, oral, transdermal, pulmonary and ocular routes using polymer-drug conjugates as delivery systems.

Expert opinion: Although polymer-conjugated drug delivery systems reported so far face severe shortcoming of being incomplete methodology and limited routes for administration (mostly concentrated in injection), some polymer carriers like poly(amidoamine) and hyaluronic acid still offer an appealing platform to deliver drug. Acquiring the particular characteristics of each polymer carrier, exploiting novel biodegradable polymer, expanding classical drug administration ways by emerging routes and developing a rational and systematic methodology to design administration routes will be the promising directions.     

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.     

Application of lipid nanoparticles to ocular drug delivery

ABSTRACT

Introduction: Although eye drops are widely used as drug delivery systems for the anterior segment of the eye, they are also associated with poor drug bioavailability due to transient contact time and rapid washout by tearing. Moreover, effective drug delivery to the posterior segment of the eye is challenging, and alternative routes of administration (periocular and intravitreal) are generally needed, the blood–retinal barrier being the major obstacle to systemic drug delivery.

Areas covered: Nanotechnology, and especially lipid nanoparticles, can improve the therapeutic efficiency, compliance and safety of ocular drugs, administered via different routes, to both the anterior and posterior segment of the eye. This review highlights the main ocular barriers to drug delivery, as well as the most common eye diseases suitable for pharmacological treatment in which lipid nanoparticles have proved efficacious as alternative delivery systems.

Expert opinion: Lipid-based nanocarriers are among the most biocompatible and versatile means for ocular delivery. Mucoadhesion with consequent increase in pre-corneal retention time, and enhanced permeation due to cellular uptake by corneal epithelial cells, are the essential goals for topical lipid nanoparticle delivery. Gene delivery to the retina has shown very promising results after intravitreal administration of lipid nanoparticles as non-viral vectors.     

Brain delivery of proteins via their fatty acid and block copolymer modifications

Abstract

It is well known that hydrophobic small molecules penetrate cell membranes better than hydrophilic molecules. Amphiphilic molecules that dissolve both in lipid and aqueous phases are best suited for membrane transport. Transport of biomacromolecules across physiological barriers, e.g. the blood-brain barrier, is greatly complicated by the unique structure and function of such barriers. Two decades ago we adopted a simple philosophy that to increase protein delivery to the brain one needs to modify this protein with hydrophobic moieties. With this general idea we began modifying proteins (antibodies, enzymes, hormones, etc.) with either hydrophobic fatty acid residues or amphiphilic block copolymer moieties, such as poy(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (pluronics or poloxamers) and more recently, poly(2-oxasolines). This simple approach has resulted in impressive successes in CNS drug delivery. We present a retrospective overview of these works initiated in the Soviet Union in 1980s, and then continued in the United States and other countries. Notably some of the early findings were later corroborated by brain pharmacokinetic data. Industrial development of several drug candidates employing these strategies has followed. Overall modification by hydrophobic fatty acids residues or amphiphilic block copolymers represents a promising and relatively safe strategy to deliver proteins to the brain.     

Current knowledge on biodegradable microspheres in drug delivery

Introduction: Biodegradable microspheres have gained popularity for delivering a wide variety of molecules via various routes. These types of products have been prepared using various natural and synthetic biodegradable polymers through suitable techniques for desired delivery of various challenging molecules. Selection of biodegradable polymers and technique play a key role in desired drug delivery.

Areas covered: This review describes an overview of the fundamental knowledge and status of biodegradable microspheres in effective delivery of various molecules via desired routes with consideration of outlines of various compendial and non-compendial biodegradable polymers, formulation techniques and release mechanism of microspheres, patents and commercial biodegradable microspheres.

Expert opinion: There are various advantages of using biodegradable polymers including promise of development with different types of molecules. Biocompatibility, low dosage and reduced side effects are some reasons why usage biodegradable microspheres have gained in popularity. Selection of biodegradable polymers and formulation techniques to create microspheres is the biggest challenge in research. In the near future, biodegradable microspheres will become the eco-friendly product for drug delivery of various genes, hormones, proteins and peptides at specific site of body for desired periods of time.     

From conventional towards new – natural surfactants in drug delivery systems design: current status and perspectives

Importance of the field: Surfactants play an important role in the development of both conventional and advanced (colloidal) drug delivery systems. There are several commercial surfactants, but a proportionally small group of them is approved as pharmaceutical excipients, recognized in various pharmacopoeias and therefore widely accepted by the pharmaceutical industry.

Areas covered in this review: The review covers some of the main categories of natural, sugar-based surfactants (alkyl polyglucosides and sugar esters) as prospective pharmaceutical excipients. It provides analysis of the physicochemical characteristics of sugar-based surfactants and their possible roles in the design of conventional or advanced drug delivery systems for different routes of administration.

What the reader will gain: Summary and analysis of recent data on functionality, applied concentrations and formulation improvements produced by alkyl polyglucosides and sugar esters in different conventional and advanced delivery systems could be of interest to researchers dealing with drug formulation.

Take home message: Recent FDA certification of an alkyl polyglucoside surfactant for topical formulation presents a significant step in the process of recognition of this relatively new group of surfactants. This could trigger further research into the potential benefits of naturally derived materials in both conventional and new drug delivery systems.     

Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs

Importance of the field: Microemulsions have been studied extensively as potential drug delivery vehicles for poorly water-soluble drugs. An understanding of the physicochemical and biopharmaceutical characteristics of the microemulsions according to administration routes will provide guidance for designing the formulations of microemulsions.

Areas covered in this review: In this paper, the use and the characteristics of microemulsions as drug delivery vehicles are reviewed. As the formulations of the microemulsion always include a great amount of surfactant and co-surfactant, which may cause hemolysis or histopathological alterations of the tissue, the potential toxicity or the irritancy of microemulsions is also discussed in this paper.

What the reader will gain: Developments of microemulsions for poorly water-soluble drugs in recent years are included in this review. Several factors limiting the commercial or clinical use of microemulsions are also discussed.

Take home message: Considering the potential in enhanced drug uptake/permeation and facing the limitations, their unique properties make microemulsions a promising vehicle for poorly water-soluble drugs.     

Lipid nanoparticles: state of the art,new preparation methods and challenges in drug delivery

Introduction: Nanoparticles are rapidly developing as drug carriers because of their size-dependent properties. Lipid nanoparticles (LNPs) are widely employed in drug delivery because of the biocompatibility of the lipid matrix.

Areas covered: Many different types of LNPs have been engineered in the last 20 years, the most important being solid lipid nanoparticles (SLNs), nanostrucured lipid carriers (NLCs), lipid–drug conjugates (LDCs) and lipid nanocapsules (LNCs). This review gives an overview of LNPs, including their physico-chemical properties and pharmacological uses. Moreover, it highlights the most important innovations in the preparation techniques of LNPs, aimed to encapsulate different molecules within the lipid matrix. Finally, it gives a short perspective on the challenges of drug delivery, which are a potential field of application for LNPs: cancer therapy, overcoming the blood–brain barrier and gene and protein delivery.

Expert opinion: LNPs are a safe and versatile vehicles for drug and active delivery, suitable for different administration routes. New technologies have been developed for LNP preparation and studies are currently underway in order to obtain the encapsulation of different drugs and to deliver the active molecule to the site of action.     

Applications of poloxamers in ophthalmic pharmaceutical formulations: an overview

Introduction: An ideal ophthalmic formulation is one that not only prolongs the contact time of the vehicle on the ocular surface but also slows down the drug elimination. The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of the drug may be overcome by the use of in situ gel forming systems. In situ gelling systems increase the viscosity by changing the pH or temperature in the pre-corneal region and lead to an increase of drug bioavailability by slowing drainage. Poloxamers are polyols with thermal gelling properties which are frequently included in ophthalmic formulations to improve the ocular bioavailability of drugs by increasing vehicle viscosity.

Areas covered: An overview on the unique physiological characteristics of ocular globe and the limitations and disadvantages of the conventional ophthalmic pharmaceutical formulations. Readers will appreciate the different strategies to improve the absorption of drugs in the ocular globe, especially the incorporation of poloxamers in ophthalmic formulations, understanding the main advantages of the poloxamers and also learning about the different examples of applications of these polymers in ophthalmic pharmaceutical formulations.

Expert opinion: Poloxamers offers a new strategy to improve bioavailability and decrease the side effects induced by the systemic absorption of topically applied ophthalmic drugs.     

Potential of nanoparticles for allergen-specific immunotherapy – use of silica nanoparticles as vaccination platform

ABSTRACT

Introduction: Allergen-specific immunotherapy is the only curative approach for the treatment of allergies. There is an urgent need for improved therapies, which increase both, efficacy and patient compliance. Novel routes of immunization and the use of more advanced vaccine platforms have gained heightened interest in this field.

Areas covered: The current status of allergen-specific immunotherapy is summarized and novel routes of immunization and their challenges in the clinics are critically discussed. The use of nanoparticles as novel delivery system for allergy vaccines is comprehensively reviewed. Specifically, the advantages of silica nanoparticles as vaccine carriers and adjuvants are summarized.

Expert opinion: Future allergen-specific immunotherapy will combine engineered hypoallergenic vaccines with novel routes of administration, such as the skin. Due to their biodegradability, and the easiness to introduce surface modifications, silica nanoparticles are promising candidates for tailor-made vaccines. By covalently linking allergens and polysaccharides to silica nanoparticles, a versatile vaccination platform can be designed to specifically target antigen-presenting cells, render the formulation hypoallergenic, and introduce immunomodulatory functions. Combining potent skin vaccination methods, such as fractional laser ablation, with nanoparticle-based vaccines addresses all the requirements for safe and efficient therapy of allergic diseases.     

Single-use disposable dry powder inhalers for pulmonary drug delivery

Importance of the field: The understanding of pulmonary drug delivery and thus its utilization for medical purposes has remarkably advanced over the last decades. It has been recognized that this route of administration offers many advantages and several drug delivery systems have been developed accordingly. Thereby, single-use disposable dry powder inhalers may be considered an economically and therapeutically valuable option for both local and systemic administration of drugs to treat a variety of different disease states.

Areas covered in this review/What the reader will gain: This review highlights the required characteristics and potential applications of single-use disposable dry powder inhalers considering advantages as well as limitations of these drug delivery devices. Until now, such drug delivery systems have not become widely accepted. Several devices are available or under development and a few products have reached or completed the clinical phase, but none of them have received market authorization as yet.

Take home message: Recent advances in formulation and device design, however, can be considered encouraging and should eventually lead to a wider establishment of single-use disposable dry powder inhalers in pulmonary drug delivery.     

Polymeric micelles for oral drug administration enabling locoregional and systemic treatments

Introduction: Amphiphilic block copolymers are recognized components of parenteral drug nanocarriers. However, their performance in oral administration has barely been evaluated to any great extent.

Areas covered: This review provides an overview of the methods used to prepare drug-loaded polymeric micelles and to evaluate their stability in gastrointestinal (GI) fluids, and then analyzes in detail recent in vitro and in vivo results about their performance in oral drug delivery. Oral administration of polymeric micelles has been tested for a variety of therapeutic purposes, namely, to increase apparent drug solubility in the GI fluids and facilitate absorption, to penetrate in pathological regions of the GI tract for locoregional treatment, to carry the drug directly toward the blood stream minimizing presystemic loses, and to target the drug after oral absorption to specific tissue or cells in the body.

Expert opinion: Each therapeutic purpose demands micelles with different performance regarding stability in the GI tract, ability to overcome physiological barriers and drug release patterns. Depending on the block copolymer composition and structure, a wealth of self-assembled micelles with different morphologies and stability can be prepared. Moreover, copolymer unimers can play a role in improving drug absorption through the GI mucosa, either by increasing membrane permeability to the drug and/or the carrier or by inhibiting drug efflux transporters or first-pass metabolism. Therefore, polymeric micelles can be pointed out as versatile vehicles to increase oral bioavailability of drugs that exhibit poor solubility or permeability and may even be an alternative to parenteral carriers when targeting is pursued.     

Poly(ethylene oxide) based copolymers: solubilisation capacity and gelation

It is thought that almost half of potentially useful drug candidates fail to progress to formulation development because of their low aqueous solubility and associated poor or erratic absorption characteristics. A response to this challenge has been the development of a variety of colloidal delivery systems in which the therapeutic agent is encapsulated in nanosized particles. In this review, attention is focussed on colloidal vectors based on amphiphilic block copolymers, the micelles of which can accommodate a wide range of water-insoluble guest molecules, and particularly on copolymers with poly(oxyethylene) as the hydrophilic block and with poly(oxyalkylene) or polyester hydrophobic blocks, taking advantage of the ‘stealth’ properties of the poly(oxyethylene) corona of their micelles. Although copolymers of this type have been commercially available for several decades in the form of the Pluronic^® (BASF) polyols, which have a poly(oxypropylene) hydrophobic block, they have not found wide application for drug solubilisation, primarily because of their low solubilisation capacity. In attempts to achieve greater drug loading, recent work has concentrated on copolymers in which the core-forming blocks are designed to be more hydrophobic and more compatible with the drug to be encapsulated. Progress in this area has been reviewed and recent developments in the design of block copolymers of this type that combine high drug loading capacity with thermally reversible gelation characteristics in the temperature range suitable for potential application as in situ gelling vehicles following subcutaneous injection have also been discussed.     

Recent advance of nanoparticle-based topical drug delivery to the posterior segment of the eye

Introduction: Considering that the number of patients afflicted by posterior eye diseases is increasing, effective drug delivery is currently in high clinical demand. Topical administration has been identified as the preferred option, while sufferingfrom multiple barriers. The development of nanoparticle-based drug delivery system provides an option, which would enhance the drug permeability across the barriers and achieve the desired drug level in the targeted tissue.

Areas covered: This review highlights the barrier to the posterior segment of the eye via topical administration. The up-to-date development of lipid nanoparticles, liposomes, emulsions, spanlastics, micelles, polymeric nanoparticles, layered double hydroxides (LDH), dendrimers, cyclodextrins(CDs), and prodrugs are summarized. Moreover, nanocarriers currently in clinical trials for posterior segment diseases have been discussed.

Expert opinion: Topical nanoparticle-based drug delivery systems have demonstrated significant progress. An ideal formulation should prolong retention time on the surface, enhance drug permeability through the ocular tissues, and efficiently deliver drugs to the targeted site. To design the rational targeting nanoparticle-based drug delivery system, a better understanding of the distribution of transporters and receptors on the eye is required. Ultimately, there is an urgent need to develop targeting hybrid drug delivery systems with the combination of the advantages of several nanocarriers.     

Nanoparticles as multifunctional devices for the topical treatment of cutaneous leishmaniasis

Introduction: Cutaneous and mucocutaneous leishmaniasis are major tropical skin diseases. Topical treatment is currently limited to the least severe forms of cutaneous leishmaniasis (CL) without risk of dissemination. It is also recommended in combination with systemic therapy for more severe forms. Progresses in this modality of treatment are hindered by the heterogeneity of the disease and shortcomings in the clinical trials.

Areas covered: This review overlooks three major modalities of topical therapies in use or under investigation against CL: chemotherapy, photodynamic therapy and immunotherapy; either with older compounds such as paramomycin or more recent nitric oxide donors, antimicrobial peptides or silver derivatives. The advantages and limitations of their administration with newer formulation strategies such as nanoparticles (NPs) are discussed.

Expert opinion: The efficacy of a topical treatment against CL depends not only on the intrinsic antileishmanial activity of the drug but also on the amount of drug available in the dermis. NPs as sustained release systems and permeation enhancers could favour the creation of a drug reservoir in the dermis. Additionally, certain NPs have immunomodulatory properties or wound healing capabilities of benefit in CL treatment. Pending task is the selective delivery of active compounds to intracellular amastigotes, because even small NPs are unable to penetrate deeply into the skin to encounter infected macrophages (except in ulcerative lesions).     

Spray-on transdermal drug delivery systems

Introduction: Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems.

Areas covered: A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.

Expert opinion: TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.     

Biodegradable block copolymers.

Recently, block copolymers have got tremendous impetus on the ongoing research in the area of drug delivery technology, due to their capability to provide a biomaterial having a broad range of amphiphilic characteristics, as well as targeting the drugs to specific site. This article is an attempt to review applications of block copolymers in surface modification, drug targeting, nano and microparticles, hydrogels, micelles etc. The physicochemical properties of block copolymers and various synthetic routes for block copolymers are also discussed.