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.     

PLGA nanoparticles in drug delivery: the state of the art

Nanoparticles represent drug delivery systems suitable for most administration routes. Over the years, a variety of natural and synthetic polymers have been explored for the preparation of nanoparticles, of which Poly(lactic acid) (PLA), Poly(glycolic acid) (PGA), and their copolymers (PLGA) have been extensively investigated because of their biocompatibility and biodegradability. Nanoparticles act as potential carries for several classes of drugs such as anticancer agents, antihypertensive agents, immunomodulators, and hormones; and macromolecules such as nucleic acids, proteins, peptides, and antibodies. The options available for preparation have increased with advances in traditional methods, and many novel techniques for preparation of drug-loaded nanoparticles are being developed and refined. The various methods used for preparation of nanoparticles with their advantages and limitations have been discussed. The crux of the problem is the stability of nanoparticles after preparation, which is being addressed by freeze-drying using different classes of lyoprotectants. Nanoparticles can be designed for the site-specific delivery of drugs. The targeting capability of nanoparticles is influenced by particle size, surface charge, surface modification, and hydrophobicity. Finally, the performance of nanoparticles in vivo is influenced by morphological characteristics, surface chemistry, and molecular weight. Careful design of these delivery systems with respect to target and route of administration may solve some of the problems faced by new classes of active molecules.     

SLN, NLC, LDC: state of the art in drug and active delivery

Drug delivery system focuses on the regulation of the in vivo dynamics, in order to improve the effectiveness and safety of the incorporated drugs by use of novel drug formulation technologies. Lipids such as fatty acids, triglycerides, vegetable oils and their derivatives, used for developing multiparticulate dosage forms, may be available in solid, semi-solid or liquid state. Solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) and lipid drug conjugate (LDCs) nanoparticles are novel lipid drug delivery systems. They were devised to address some of the challenges of conventional drug delivery systems ranging from low drug encapsulation efficiency to low bioavailability of Biopharmaceutical Classification Systems (BCS) class II and class IV drugs. SLNs are based on melt-emulsified lipids, which are solid at room temperature and consist of physiologically well tolerated ingredients often generally recognised as safe. NLCs are colloidal carriers characterized by a solid lipid core consisting of a mixture of solid and liquid lipids, and having a mean particle size in the nanometer range. LDC are nanoparticles contain drugs linked to lipid particles. This minireview highlights these three different but related technologies in lipid drug delivery. The objectives of their introduction, current applications, major challenges and some patented formulations are highlighted.     

Janus nanoparticles: materials,preparation and recent advances in drug delivery

Introduction: The term Janus particles was used to describe particles that are the combination of two distinct sides with differences in chemical nature and/or polarity on each face. Due to the exponential growth of interest on multifunctional nanotechnologies, such anisotropic nanoparticles are promising tools in the field of drug delivery.

Areas covered: The main preparation processes and the materials used have been described first. Then a specific focus has been done on therapeutic and/or diagnostic applications of Janus particles.

Expert opinion: Janus particles are demonstrated as interesting objects with advanced properties that combine features and functionalities of different materials in one single unit. Due to their dual structure, Janus particles are promising candidates for a variety of high-quality applications dealing with drug delivery purposes. Still, the main challenges for the future lie in the development of the preparation of shape-controlled and nano-sized particles with large-scale production processes and approved pharmaceutical excipients.     

Lipid nanoparticles for cancer therapy: state of the art and future prospects

Introduction: Cancer is a leading cause of death worldwide and it is estimated that deaths from this disease will rise to over 11 million in 2030. Most cases of cancer can be cured with surgery, radiotherapy or chemotherapy if they are detected at an early stage. However, current cancer therapies are commonly associated with undesirable side effects, as most chemotherapy treatments are cytotoxic and present poor tumor targeting.

Areas covered: Lipid nanoparticles (LN) are one of the most promising options in this field. LN are made up of biodegradable generally recognized as safe (GRAS) lipids, their formulation includes different techniques, and most are easily scalable to industrial manufacture. LN overcome the limitations imposed by the need for intravenous administration, as they are mainly absorbed via the lymphatic system when they are administered orally, which improves drug bioavailability. Furthermore, depending on their composition, LN present the ability to cross the blood–brain barrier, thus opening up the possibility of targeting brain tumors.

Expert opinion: The drawbacks of chemotherapeutic agents make it necessary to invest in research to find safer and more effective therapies. Nanotechnology has opened the door to new therapeutic options through the design of formulations that include a wide range of materials and formulations at the nanometer range, which improve drug efficacy through direct or indirect tumor targeting, increased bioavailability and diminished toxicity.     

纳米粒给药系统制备的研究进展

纳米给药系统在实现药物靶向给药,缓、控释放等方面表现出良好的应用前景,因而成为近年来药剂学领域的研究热点之一.本文综述了纳米粒(纳米球和纳米囊)的主要制备方法及其优缺点,并对纳米粒主动靶向修饰的手段进行了归纳.     

Lipid nanoparticles: Different preparation techniques,characterization, hurdles,and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery

The bioavailability of an orally administered drug primarily depends on its solubility in the GIT and its permeability across cell membranes. Also, a drug in solution form is preferred for conducting pharmacological, toxicological and pharmacokinetic studies during the drug development stage. Thus, poor water solubility not only limits a drug’s biological application but also challenges its pharmaceutical development. The use of lipid nanoparticles (LNs) in pharmaceutical technology has been reported for several years due to its important in green chemistry for several reasons specifically for its biochemical as “green” materials and biochemical processes as green processes that can be very environmentally friendly. Also, the physiological/physiologically related lipids (GRAS) made LNs usually enhance the drug absorption in the GIT. Hence, the pathways for absorption, metabolism, and transportation are present in the body, which may contribute to a large extent to the bio-fate of the lipidic carrier. Moreover, the LNs improves the mucosal adhesion and increases their GIT residence time. The LNs with a solid matrix are two types: solid lipid nanoparticle (SLN) and nanostructured lipid carrier (NLC). Also, their hydrophobic core provides a suitable environment for entrapment of hydrophobic drugs to improve its bioavailability. This review highlights and discusses the simple and easily scaled-up novel SLN and NLC along with their different production techniques, hurdles, and strategies for the production of LNs, characterization, lyophilization and drug release. Also, this review summarizes the research findings reported by the different researchers regarding the different method of preparation, excipients and their significant findings.     

Molecularly imprinted polymers in drug delivery: state of art and future perspectives

Introduction: Molecularly imprinted polymers (MIPs) are synthetic receptors, characterized by a high selectivity for the selected template. Among the different applications of MIPs, their use as controlled/sustained drug delivery devices has been extensively explored, even though the optimization of such devices needs to be performed before they are applied in clinical practice.

Areas covered: Within drug delivery, one of the most promising fields is the possibility to modulate the drug release profile in response to a specific external stimulus; MIPs represent potentially suitable vehicles, because of the possibility to insert a stimuli-responsive co-monomer in their structure. This review discusses recent advances in the use of external stimuli to modulate drug release, as well as the synthetic strategies devoted to increase the water compatibility of these systems, which is a base requirement for their application in biomedicine.

Expert opinion: Although it is easy to imagine imprinted polymers for biomedical applications, several aspects have to be further investigated, such as the in vivo studies, efficiency and biocompatibility. However, we think that in the next few years it will possible to see unprecedented progress in the preparation of such systems and the translational application of these intelligent structures in medicine.     

Molecularly imprinted polymers in drug delivery: state of art and future perspectives

INTRODUCTION: Molecularly imprinted polymers (MIPs) are synthetic receptors, characterized by a high selectivity for the selected template. Among the different applications of MIPs, their use as controlled/sustained drug delivery devices has been extensively explored, even though the optimization of such devices needs to be performed before they are applied in clinical practice. AREAS COVERED: Within drug delivery, one of the most promising fields is the possibility to modulate the drug release profile in response to a specific external stimulus; MIPs represent potentially suitable vehicles, because of the possibility to insert a stimuli-responsive co-monomer in their structure. This review discusses recent advances in the use of external stimuli to modulate drug release, as well as the synthetic strategies devoted to increase the water compatibility of these systems, which is a base requirement for their application in biomedicine. EXPERT OPINION: Although it is easy to imagine imprinted polymers for biomedical applications, several aspects have to be further investigated, such as the in vivo studies, efficiency and biocompatibility. However, we think that in the next few years it will possible to see unprecedented progress in the preparation of such systems and the translational application of these intelligent structures in medicine.     

Surface functionalization of polymeric nanoparticles for tumor drug delivery: approaches and challenges

Introduction: For years, injectable polymeric nanoparticles (NPs) have been developed for delivering therapeutic agents to the tumors. Frequently, NPs surface have been modified with different moieties and/or ligands to impart stealth effect and/or elicit specific cellular interactions, both known to dramatically affect the in vivo fate and efficacy of these NPs.

Areas covered: We discuss different types of ligands and molecules used for surface functionalization of polymeric NPs for tumor drug delivery. First, we summarize methods used through the literature for surface modification of polymeric NPs, then discuss challenges that face researchers either in decorating NPs with desired surface functionalities, characterizing functionalized surfaces or achieving intended cellular interactions and in vivo effects.

Expert opinion: Modification of NP surfaces dramatically alters their behavior and favorably enhances their therapeutic efficacy. Choice of surface ligand/functionality should be based on intended therapeutic outcomes, taking into consideration the potential of clinical translation and scale up of the developed systems.     

Nanostructured materials in drug and gene delivery: a review of the state of the art

A wide variety of drug delivery systems have been developed, each with its own advantages and limitations, but the important goals of all of the systems are to enhance bioavailability, reduce drug toxicity, target to a particular organ, and increase the stability of the drug. The development of nanostructured drug carriers have grasped increased attention from scientific and commercial organizations due to their unique ability to deliver drugs and challenging molecules such as proteins and nucleic acids. These carriers present many technological advantages such as high carrier capacity, high chemical and biological stability, feasibility of incorporating both hydrophilic and hydrophobic substances, and their ability to be administered by a variety of routes (including oral, inhalational, and parenteral) to provide controlled/sustained drug release. Moreover, applications of nanoparticulate formulations in enhancing drug solubility, dissolution, bioavailability, safety, and stability have already been proven. In the view of their multifaceted applications, the present review aims to discuss and summarize some of the interesting findings and applications, methods of preparation, and characterization of various nanostructured carriers useful in drug delivery. Included in this discussion are polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, dendrimers, cyclodextrins, fullerenes, gold and silica nanoparticles, and quantum dots. Because there are likely to be new applications for nanoparticles in drug delivery, they are expected to solve many problems associated with the delivery of drugs and biomolecules through different delivery routes.     

Novel methods of targeted drug delivery: the potential of multifunctional nanoparticles

Nanomaterials have been demonstrated as useful tools for molecular imaging, molecular diagnosis and targeted therapy in biomedical research. The main advantages of such nanomaterials are improved circulation times, precise targeting, enhancement of dissolution rates and enhanced contrast. A challenge and opportunity for nanotechnological strategies is that multiple functionalities, such as therapeutics, targeting, imaging and stimuli responsiveness can be achieved within one nanoparticle. Multifunctional nanoparticles are now actively under investigation and are imminent as the next generation of nanoparticles for providing custom and tailored treatment. This review considers contemporary approaches and possible future directions in the emerging area of multifunctional nanoparticles with a special focus on targeted drug delivery.     

Advances in brain drug targeting and delivery: limitations and challenges of solid lipid nanoparticles

Introduction: With the advancement in the field of medical colloids and interfacial sciences, the life expectancy has been greatly improved. In addition, changes in the human lifestyle resulted in development of various organic and functional disorders. Central nervous system (CNS) disorders are most prevalent and increasing among population worldwide. The neurological disorders are multi-systemic and difficult to treat as portal entry to brain is restricted on account of its anatomical and physiological barrier.

Areas covered: The present review discusses the limitations to CNS drug delivery, and the various approaches to bypass the blood brain barrier (BBB), focusing on the potential use of solid lipid nanoparticles (SLN) for drug targeting to brain. The methods currently in use for SLN production, physicochemical characterization and critical issues related to the formulation development suitable for targeting brain are also discussed.

Expert opinion: The potential advantages of the use of SLN over polymeric nanoparticles are due to their lower cytotoxicity, higher drug loading capacity and scalability. In addition, their production is cost effective and the systems provide a drug release in a controlled manner up to several weeks. Drug targeting potential of SLN can be enhanced by attaching ligands to their surface.     

Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art.

Solid lipid nanoparticles (SLN) introduced in 1991 represent an alternative carrier system to traditional colloidal carriers, such as emulsions, liposomes and polymeric micro- and nanoparticles. SLN combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews the present state of the art regarding production techniques for SLN, drug incorporation, loading capacity and drug release, especially focusing on drug release mechanisms. Relevant issues for the introduction of SLN to the pharmaceutical market, such as status of excipients, toxicity/tolerability aspects and sterilization and long-term stability including industrial large scale production are also discussed. The potential of SLN to be exploited for the different administration routes is highlighted. References of the most relevant literature published by various research groups around the world are provided.     

Transdermal drug delivery: progress and challenges

There are a number of advantages associated with transdermal drug delivery. With this route of administration, it is possible to avoid pain and presystemic metabolism. In addition, pharmacokinetic profile of the drug is more uniform with fewer peaks and troughs. However, the outermost layer of the skin. the stratum corneum. constitutes a strong barrier making it difficult for permeants to cross the skin at clinically relevant rates. This review examines progress made over the last 4 decades and challenges ahead. Over this period, about 35 transdermal products have been approved by regulatory authorities. About 19 drugs have been formulated into transdermal patches and approved by the Food and Drug Administration. The main challenge lies with the formulation of macromolecules- proteins, small interfering RNA and other products of biotechnology into transdermal delivery systems. This challenge is being met with approaches such as microneedles, iontophoresis, sonophoresis and electroporation.     

Potential new methods for antiepileptic drug delivery

Use of novel drug delivery methods could enhance the efficacy and reduce the toxicity of antiepileptic drugs (AEDs). Slow-release oral forms of medication or depot drugs such as skin patches might improve compliance and therefore seizure control. In emergency situations, administration via rectal, nasal or buccal mucosa can deliver the drug more quickly than can oral administration. Slow-release oral forms and rectal forms of AEDs are already approved for use, nasal and buccal administration is currently off-label and skin patches for AEDs are an attractive but currently hypothetical option. Therapies under development may result in the delivery of AEDs directly to the regions of the brain involved in seizures. Experimental protocols are underway to allow continuous infusion of potent excitatory amino acid antagonists into the CSF. In experiments with animal models of epilepsy, AEDs have been delivered successfully to seizure foci in the brain by programmed infusion pumps, acting in response to computerised EEG seizure detection. Inactive prodrugs can be given systemically and activated at the site of the seizure focus by locally released compounds. One such drug under development is DP-VPA (or DP16), which is cleaved to valproic acid (sodium valproate) by phospholipases at the seizure focus. Liposomes and nanoparticles are engineered micro-reservoirs of a drug, with attached antibodies or receptor-specific binding agents designed to target the particles to a specific region of the body. Liposomes in theory could deliver a high concentration of an AED to a seizure focus. Penetration of the blood-brain barrier can be accomplished by linking large particles to iron transferrin or biological toxins that can cross the barrier. In the near future, it is likely that cell transplants that generate neurotransmitters and neuromodulators will accomplish renewable endogenous drug delivery. However, the survival and viability of transplanted cells have yet to be demonstrated in the clinical setting. Gene therapy also may play a role in local drug delivery with the use of adenovirus, adeno-associated virus, herpesvirus or other delivery vectors to induce brain cells to produce local modulatory substances. New delivery systems should significantly improve the therapeutic/toxic ratio of AEDs.