Drug delivery from gelatin-based systems

Introduction: Carriers for controlled drug release offer many advantages compared with conventional dosage forms. Gelatin has been investigated extensively as a drug delivery carrier, due to its properties and history of safe use in a wide range of medical applications.

Areas covered: Gelatin was shown to be versatile due to its intrinsic features that enable the design of different carrier systems, such as microparticles and nanoparticles, fibers and even hydrogels. Gelatin microparticles can serve as vehicles for cell amplification and for delivery of large bioactive molecules, whereas gelatin nanoparticles are better suited for intravenous delivery or for drug delivery to the brain. Gelatin fibers contain a high surface area-to-volume ratio, whereas gelatin hydrogels can trap molecules between the polymer’s crosslink gaps, allowing these molecules to diffuse into the blood stream. Another interesting area is the combination of tissue bioadhesive-based gelatin with controlled drug release for pain management and wound healing.

Expert opinion: The modification of gelatin and its combinations with other biomaterials have demonstrated the flexibility of these systems and can be employed for meeting the challenges of finding ideal carrier systems that enable specific, targeted and controlled release in response to demands in the body.     

Nanostructured lipid carriers (NLCs) versus solid lipid nanoparticles (SLNs) for topical delivery of meloxicam

Abstract

Objective: The aim of this study was to develop nanostructured lipid carriers (NLCs) as well as solid lipid nanoparticles (SLNs) and evaluate their potential in the topical delivery of meloxicam (MLX).

Materials and methods: The effect of various compositional variations on their physicochemical properties was investigated. Furthermore, MLX-loaded lipid nanoparticles-based hydrogels were formulated and the gels were evaluated as vehicles for topical application.

Results and discussion: The results showed that NLC and SLN dispersions had spherical shapes with an average size between 215 and 430?nm. High entrapment efficiency was obtained ranging from 61.94 to 90.38% with negatively charged zeta potential in the range of ?19.1 to ?25.7?mV. The release profiles of all formulations exhibited sustained release characteristics over 48?h and the release rates increased as the amount of liquid lipid in lipid core increased. Finally, Precirol NLC with 50% Miglyol® 812 and its corresponding SLN were incorporated in hydrogels. The gels showed adequate pH, non-Newtonian flow with shear-thinning behavior and controlled release profiles. The biological evaluation revealed that MLX-loaded NLC gel showed more pronounced effect compared to MLX-loaded SLN gel.

Conclusion: It can be concluded that lipid nanoparticles represent promising particulate carriers for topical application.     

Guar gum as platform for the oral controlled release of therapeutics

Introduction: The past decade of research has witnessed a huge advancement in research efforts on guar gum (GG)-based polymers as controlled release (CR) formulations for the delivery of therapeutics.

Areas covered: The unique structure and beneficial properties of GG makes it an attractive biomaterial in CR applications. Current status on GG-based polymers has been addressed as a CR formulation in the form of microspheres, nanoparticles, hydrogels and matrix tablets for the delivery of various types of therapeutics having a wide range of physicochemical properties. Majority of literature on GG as a platform technology has dealt with oral route of drug administration as it is the most convenient, patient-compliant and preferred approach. Recent reports on GG-based polymers are summarized and critically discussed to narrate their usefulness as oral delivery systems.

Expert opinion: The research on GG-based formulations has been focused on optimization of the therapy by designing CR dosage forms with a minimum number of excipients. In this context, GG-based polymers are quite attractive. The present review summarizes published reports on these systems and offers expert opinion relevant to oral delivery of therapeutics.     

Solid lipid microparticles as an approach to drug delivery

Introduction: Solid lipid particles were introduced in the early 1990s as an alternative drug carrier system to emulsions, liposomes and polymeric microparticles. Although lipid nanoparticles have been the object of a substantial number of reviews, fewer are available on lipid microparticles (LMs), despite their distinct advantages, including biocompatibility, ease of production and characterisation, extended release properties and high loading.

Areas covered: This review presents an overview of the advantages and drawbacks of LMs, that is, lipid-based particles with dimensions in the micrometre range. Specific focus is on the role of the main excipients used for LM formulations, lipids and surfactants and their effects on LM properties. An update on preparation techniques and characterisation methods are also presented, with particular emphasis on more recent technologies. The interaction of LMs with biological systems and with cells in particular is reviewed. The various LM administration routes are examined, with special attention to most recent applications (i.e., pulmonary and nasal delivery).

Expert opinion: LMs represent attractive and versatile carrier systems; however, their pharmaceutical applicability has been rather limited. Investigation on the use of LMs for less-established administration routes, such as pulmonary delivery, may provide further interest within the area of LM-based systems, both in industry and in the clinic.     

Micro and nanosystems for delivering local anesthetics

Introduction: One of the most common strategies for pain control during and after surgical procedures is the use of local anesthetics. Prolonged analgesia can be safely achieved with drug delivery systems suitably chosen for each local anesthetic agent.

Areas covered: This review considers drug delivery formulations of local anesthetics designed to prolong the anesthetic effect and decrease toxicity. The topics comprise the main drug delivery carrier systems (liposomes, biopolymers, and cyclodextrins) for infiltrative administration of local anesthetics. A chronological review of the literature is presented, including details of formulations as well as the advantages and pitfalls of each carrier system. The review also highlights pharmacokinetic data on such formulations, and gives an overview of the clinical studies published so far concerning pain control in medicine and dentistry.

Expert opinion: The design of novel drug delivery systems for local anesthetics must focus on how to achieve higher uploads of the anesthetic into the carrier, and how to sustain its release. This comprehensive review should be useful to provide the reader with the current state-of-art regarding drug delivery formulations for local anesthetics and their possible clinical applications.     

Drug delivery systems for differential release in combination therapy

Introduction: Combination therapy with multiple therapeutic agents has wide applicability in medical and surgical treatment, especially in the treatment of cancer. Thus, new drug delivery systems that can differentially release two or more drugs are desired. Utilizing new techniques to engineer the established drug delivery systems and synthesizing new materials and designing carriers with new structures are feasible ways to fabricate proper multi-agent delivery systems, which are critical to meet requirements in the clinic and improve therapeutic efficacy.

Areas covered: This paper aims to give an overview about the multi-agent delivery systems developed in the last decade for differential release in combination therapy. Multi-agent delivery systems from nanoscale to bulk scale, such as liposomes, micelles, polymer conjugates, nano/micorparticles and hydrogels, developed over the last 10 years, have been collected and summarized. The characteristics of different delivery systems are described and discussed, including the structure of drug carriers, drug-loading techniques, release behaviors and consequent evaluation in biological assays.

Expert opinion: The chemical structure of drug delivery systems is the key to controlling the release of therapeutic agents in combination therapy, and the differential release of multiple drugs could be realized by the successful design of a proper delivery system. Besides biological evaluation in vitro and in vivo, it is important to speed up practical application of the resulting delivery systems.     

Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and nanopharmaceuticals

Introduction: Compritol® 888 ATO is a lipid excipient that is generally used in cosmetic industry as a surfactant, emulsifying agent and viscosity-inducing agent in emulsions or creams. Based on its chemical composition, Compritol 888 ATO is a blend of different esters of behenic acid with glycerol.

Areas covered: Recently, there has been great interest in the multiple roles that Compritol 888 ATO plays in various pharmaceutical delivery systems. Accordingly, this review aimed at summarizing the current and potential applications of Compritol 888 ATO in various drug delivery areas.

Expert opinion: Different researches have highlighted the feasibility of using Compritol 888 ATO as a lubricant or coating agent for oral solid dosage formulations. It has also been explored as a matrix-forming agent for controlling drug release. At present, the most common pharmaceutical application of Compritol 888 ATO is in lipid-based colloidal drug delivery system such as solid lipid microparticles, solid lipid nanoparticles and nanostructured lipid carriers. Although, Compritol 888 ATO has acceptable regulatory and safety profiles and although the number of articles that emphasize on its applicability as an innovative excipient in pharmaceutical technology is continuously increasing, it is not widely used in the pharmaceutical market products and its use is limited to its sustain release ability in extended release tablets.     

Thermosensitive hydrogels for drug delivery

Introduction: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels.

Areas covered: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration.

Expert opinion: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

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.     

Nanomedicines for ocular NSAIDs: safety on drug delivery

The eyes are among the most readily accessible organs in terms of location in the body, yet drug delivery to eye tissues is particularly problematic. Poor bioavailability of drugs from ocular dosage forms is mainly due to precorneal loss factors (e.g., tear dynamics, nonproductive absorption, transient residence time in the cul-de-sac, and relative impermeability of the corneal epithelial membrane). There is a clear need for effective topical formulations capable of promoting drug penetration and maintaining therapeutic levels with a reasonable frequency of application—a strategy that can also result in enhancement of side effects that probably would not be acceptable. Delivery of a drug via a nanotechnology-based product fulfills three main objectives: enhancement of drug permeation, controlled release, and targeting. The inflammatory response of the ocular tissues is a common side effect associated with ophthalmic surgery. Together with steroidal agents, nonsteroidal anti-inflammatory drugs are used in eye surgery. In this review we focus on microemulsions, polymeric nanoparticles, liposomes, solid lipid nanoparticles, and drug nanocrystals as formulations incorporating anti-inflammatory drugs for ophthalmic application.From the Clinical EditorThis review focuses on microemulsions, polymeric nanoparticles, liposomes, solid lipid nanoparticles, and drug nanocrystals as novel high efficiency delivery systems of anti-inflammatory drugs in ophthalmic applications.     

Chemical and technological delivery systems for idebenone: a review of literature production

Introduction: Idebenone (IDE) is an antioxidant compound, structurally related to coenzyme Q10. Its therapeutic potential is growing in different application areas, as demonstrated by the number of experimental works and patents produced in very recent years.

Areas covered: Cyclodextrin inclusion complexes, liposomes, microemulsions, prodrugs, polymeric and lipid nanoparticles have been explored to achieve different goals, such as topical administration, brain targeting or increasing the bioavailability of this highly lipophilic drug. This review summarizes the results of works published in the last 20 years for the delivery and targeting of this drug.

Expert opinion: A direct comparison of the different carrier systems is not easy and could not even be significant, due to the large variables existing among them. However, the different forms of delivery can help increase idebenone solubility, stability and biochemical activity. Further studies will be developed in order to improve the controlled release and targeting of idebenone.     

Polyacrylic acid polymers hydrogels intended to topical drug delivery: preparation and characterization

Abstract

Context: Bioadhesiviness of polyacrylic acid polymers make them promising hydrogels to design topical drug delivery systems, allowing a close contact with biological substrate as well as an enhanced local concentration gradient, both factors that may improve the biological performance of the drugs.

Aim: Texture and bioadhesive properties of hydrogels were assessed by using texture analyzer and they were correlated with their rheological behavior and performance as drug delivery systems.

Methods: Aqueous dispersions of both polymers were prepared at 0.5%, 1.0% and 1.5% w/v. Hardness, compressibility, adhesiveness, cohesiveness, bioadhesion, continuous flow, oscillatory dynamic test and in vitro drug release were evaluated.

Results: Rheological and texture parameters were dependent on polymer concentration and C974P polymer built the strongest structures. Both 1.5% hydrogels presented high bioadhesion values. About 50% of the metronidazole (MTZ) was sustained released from hydrogels within 2?h with an initial burst release at early stage. After, the release rates were decreased and 10% of the MTZ was released in the next 10?h. The drug release process was driven by Fickian diffusion and complex mechanism for PP and C974P hydrogels, respectively.

Conclusion: The set of results demonstrated that these hydrogels are promising to be used as topical controlled drug delivery system.     

Future of nanomedicines for treating respiratory diseases

Introduction: Nanoparticles are under discussion in drug delivery for more than 20 years now, but examples for nanoparticulate formulations in the treatment of respiratory diseases are rare and mostly limited to the administration of sub-micron drug particles (ultrafine particles). However, nanoparticles may also carry specific benefits for respiratory treatment. Are nanoparticles the next-generation drug carrier system to facilitate systemic delivery, sustained release and cancer treatment in the lungs?

Areas covered: This review will look into the promises and opportunities of the use of nanoparticles in the treatment of respiratory diseases. Important aspects to discuss are the fate of nanoparticles in the lung and mechanisms for reproducible delivery of nanoparticulate formulations to the lungs. Examples are given where nanoparticles may be advantageous over for traditional formulations and further aspects to explore are mentioned.

Expert opinion: The benefit of nanoparticulate systems for respiratory delivery adds to the portfolio of possible formulation strategies, depends on the intended functionality and needs more exploration. Advantages of such systems are only seen in special cases.     

5-Fluorouracil in topical liposome gels for anticancer treatment--formulation and evaluation

Liposome gels bearing an antineoplastic agent, 5-fluorouracil, intended for topical application have been prepared and drug release properties in vitro have been evaluated. Different formulations of liposomes were prepared by the film hydration method by varying the lipid phase composition (PL 90H/cholesterol mass ratio) and hydration conditions of dry lipid film (drug/aqueous phase mass ratio). Topical liposome gels were prepared by incorporation of lyophilized liposomes into a structured vehicle (1%, m/m, chitosan gel base). Also, hydrogels containing different concentrations of 5-fluorouracil were prepared and drug release properties were investigated. The rate of drug release from liposome gels was found to be dependent on the bilayer composition and the dry lipid film hydration conditions. Also, liposomes embedded into a structured vehicle of chitosan showed significantly slower release than hydrogels. The drug release obeyed the Higuchi diffusion model, while liposomes acted as reservoir systems for continuous delivery of the encapsulated drug.     

Drug-in-cyclodextrin-in-liposomes: a promising delivery system for hydrophobic drugs

Introduction: Recently, the entrapment of hydrophobic drugs in the form of water-soluble drug–cyclodextrin (CD) complex in liposomes has been investigated as a new strategy to combine the relative advantages of CDs and liposomes into one system, namely drug-in-CD-in-liposome (DCL) systems.

Areas covered: For DCLs preparation, an overall understanding of the interaction between CDs and lipid components of liposomes is necessary and valuable. The present article reviews the preparation, characterization and application of DCLs, especially as antitumor or transdermal carriers. Double-loading technique, an interesting strategy to control release and increase drug-loading capacity, is also discussed.

Expert opinion: DCL approach can be useful in increasing drug solubility and vesicles stability, in controlling the in vivo fate of hydrophobic drugs and in avoiding burst release of drug from the vesicles. To obtain stable DCL, the CDs should have a higher affinity to drug molecules compared with liposomal membrane lipids. DCLs prepared by double-loading technique seem to be a suitable targeted drug delivery system because they have a fast onset action with prolonged drug release process and the significantly enhanced drug-loading capacity. In particular, DCLs are suitable for the delivery of hydrophobic drugs which also possess volatility.     

Physical hydrogels with self-assembled nanostructures as drug delivery systems

Introduction: As an essential complement to chemically crosslinked hydrogels, drug delivery systems based on physical hydrogels with self-assembled nanostructures are gaining increasing attention, owing to potential advantages of reduced toxicity, convenience of in situ gel formation, stimuli-responsiveness, reversible sol-gel transition, and improved drug loading and delivery profiles.

Areas covered: In this review, drug delivery systems based on physical hydrogels are discussed according to their self-assembled nanostructures, such as micelles, layer-by-layer constructs, supramolecular inclusion complexes, polyelectrolyte complexes and crystalline structures. The driving forces of the self-assembly include hydrophobic interaction, hydrogen bonding, electrostatic interaction, π–π stacking and weak van der Waals forces. Stimuli-responsive properties of physical hydrogels, including thermo- and pH-sensitivity, are considered with particular focus on self-assembled nanostructures.

Expert opinion: Fabricating self-assembled nanostructures in drug delivery hydrogels, via physical interactions between polymer–polymer and polymer–drug, requires accurately controlled macro- or small molecular architecture and a comprehensive knowledge of the physicochemical properties of the therapeutics. A variety of nanostructures within hydrogels, with which payloads may interact, provide useful means to stabilize the drug form and control its release kinetics.     

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.     

Advances in non-invasive drug delivery for atherosclerotic heart disease

Introduction: Apart from statins, anti-platelet agents and invasive procedures, the anti-atherosclerotic medical weaponry for coronary heart disease (CHD) is scarce and only partially protects CHD patients from major adverse cardiac events.

Areas covered: Several novel non-invasive strategies are being developed to widen the therapeutic options. Among them, drug delivery tools were tested in vivo encompassing liposomes, micelles, polymeric, metallic and lipid nanoparticles used as carriers of statins, corticosteroids, a bisphosphonate, a glitazone, anti-cancer agents, a mycotoxin, a calcium channel blocker and a compound of traditional Chinese medicine. All preparations improved parameters related to atherosclerotic lesions induced in rabbits, rats and mice and reduced neointima formation in experiments aiming to prevent post-stenting restenosis. In subjects submitted to percutaneous coronary intervention, nanoparticle formulations of paclitaxel and alendronate showed safety but are still not conclusive regarding in-stent late loss. The experience of our group in atherosclerotic rabbits treated with non-protein lipid nanoparticles associated with anti-cancer drugs such as paclitaxel, etoposide and methotrexate is summarized, and preliminary safety data in CHD patients are anticipated.

Expert opinion: Taken together, these studies show that non-invasive drug-delivery systems may become promising tools to rescue CHD patients from the risks of severe and life-threatening lesions that should be more energetically treated.     

Erythrocytes-based synthetic delivery systems: transition from conventional to novel engineering strategies

Introduction: Erythrocytes (red blood cells [RBCs]) and artificial or synthetic delivery systems such as liposomes, nanoparticles (NPs) are the most investigated carrier systems. Herein, progress made from conventional approach of using RBC as delivery systems to novel approach of using synthetic delivery systems based on RBC properties will be reviewed.

Areas covered: We aim to highlight both conventional and novel approaches of using RBCs as potential carrier system. Conventional approaches which include two main strategies are: i) directly loading therapeutic moieties in RBCs; and ii) coupling them with RBCs whereas novel approaches exploit structural, mechanical and biological properties of RBCs to design synthetic delivery systems through various engineering strategies. Initial attempts included coupling of antibodies to liposomes to specifically target RBCs. Knowledge obtained from several studies led to the development of RBC membrane derived liposomes (nanoerythrosomes), inspiring future application of RBC or its structural features in other attractive delivery systems (hydrogels, filomicelles, microcapsules, micro- and NPs) for even greater potential.

Expert opinion: In conclusion, this review dwells upon comparative analysis of various conventional and novel engineering strategies in developing RBC based drug delivery systems, diversifying their applications in arena of drug delivery. Regardless of the challenges in front of us, RBC based delivery systems offer an exciting approach of exploiting biological entities in a multitude of medical applications.