Recent Patents on Drug Delivery & Formulation - Volume 5, Issue 3, 2011

INTRODUCTION Owing to lipid biocompatibility and versatility, lipid nanoparticles showed many advantages over polymeric nanoparticles and liposomes, and have been widely used for the preparation of nanoparticles for drugs and actives delivery [1]. The most known formulation in this field are solid lipid nanoparticles (SLN) [2]. Lipid nanoparticles of new generation have been lately exploited and patented, including nanostructured lipid carriers (NLC) [3] and lipid drug conjugates (LDC) [4]: all these lipid nanoparticles are produced mainly according to hot homogenisation method, which generally implies the use of an high pressure homogeniser (HPH). Many applications have been developed and patented regarding solid lipid nanoparticles: some of them are in cosmetic field, since the time-to-market is very short for these products [5-7]. Anyway, other applications are in emerging challenges of pharmaceutical field [8-11]. An innovative reformulation of a drug could extend its patent life: new delivery systems for out of patent molecules could lead to reduced side effects, achieving a more effective therapy [12]. Recently, the need of overcoming the critical process parameters of hot homogenisation technique (high temperatures, high pressures and cavitation forces) led to develop new methods to prepare lipid nanoparticles. Different techniques based on microemulsion templates have been worked out [13,14]; coacervation has been proposed for the preparation of fatty acid nanoparticles [15,16]; the potential application of phase inversion temperature has been exploited for lipid nanocapsules production [17]. Solvent based methods have been proposed, too, even if their future perspectives are limited by toxicity issues: solvent injection method [18,19], solvent evaporation method [20] and solvent diffusion method [21] have been extensively studied in literature. Also supercritical fluid (SCF) technology, in particular supercritical fluid extraction from emulsion (SFEE), has gained increasing interest for lipid nanoparticles suspension preparation [22]. Lipid nanoparticles are usually in the form of water suspensions; however, in order to comply the need of anhydrous delivery systems for various pharmaceutical applications, powdered lipid nano and microparticles have been engineered, too, according to different methods: spray-drying [23], spray-congealing [24-26], electrohydrodynamic atomisation [27, 28], cryogenic micronisation [29], rapid expansion of supercritical solutions (RESS), supercritical anti-solvent, particles from gas-saturated solutions/suspensions (PGSS) [30-32]. Currently, one of the major challenges for nanoparticles is the delivery of complex molecules, like proteins, peptides and nucleic acids (plasmid DNA, antisense oligonucleotides, short interfering RNA), with relevant stability and bioavailability problems. Naked nucleic acids are easily digested by enzymes in vivo and are not internalised by cells: lipid nanoparticles can protect them in biological fluids and have shown to enter into the cells by endocytosis [33], but suitable strategies are necessary to load these macromolecules within nanoparticles, most of them regarding the use of cationic lipids or nanoparticles with a positive surface charge [34-37]. Therapeutic application of peptides and proteins is restricted by their high molecular weight, their hydrophilic character and limited chemical stability, which cause low bioavailability, poor transfer across biological membranes and low stability in the bloodstream: lipid nanoparticles can stabilise loaded peptides and promote peptide absorption through biological membranes [38]. Different strategies have been implemented and patented for peptide and protein loading into lipid nanoparticles [38-41], including hydrophobic ion pairing technique [42]. SLN can be useful also as adjuvant for vaccine therapy [43,44]. In this issue, Attama examines the most important applications regarding SLN, NLC and LDC, while Lai et al. review the most innovative techniques, apart from hot homogenisation, for the preparation of lipid nanoparticles. Berton et al. provide a description of the methods and pharmaceutical challenges of lipid nano and microparticles in powdered form. Finally Del Pozo- Rodriguez et al. analyse two of the most important future outcomes of lipid nanoparticles: nucleic acid and protein delivery. This special issue aims to discuss, for academics as well as industrial practitioners, the recent patents on core topics of lipid nano and microparticles technology, thereby evidencing the potential economic impact of this research field. ACKNOWLEDGEMENTS We kindly acknowledge Dr. Lucia Gastaldi (Universita degli Studi di Torino - Dipartimento di Scienza e Tecnologia del Farmaco) for the supervision of the manuscripts.....

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 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.

This review details articles and recent patents in an emerging topic called powdered form of nano- and microparticles. Solid lipid particles were developed in the early 1990s and since, they have been considered as promising drug delivery systems, especially in providing a sustained release profile of the encapsulated drug. This kind of drug delivery system has several advantages, due to its physiological composition. It is generally well tolerated by the human body and are relatively stable during storage in comparison with other carriers like liposomes. The description of these powdered lipid particles, their different production processes and their applications are the focus of the article.

Lipid nanoparticles have attracted many researchers during recent years due to the excellent tolerability and advantages compared to liposomes and polymeric nanoparticles. High pressure homogenization is the main technique used to prepare solid lipid nanoparticles (SLN) encapsulating different type of drugs, however this method involves some critical process parameters. For this reason and in order to overcome patented methods, different production techniques for lipid nanoparticles have been widely investigated in recent years (last decade). The paper reviews new methods for lipid nanoparticles preparation, and their recent applications in pharmaceutical field, especially focusing on coacervation, microemulsions templates, supercritical fluid technology, phase-inversion temperature (PIT) techniques. References of the most relevant literature and patents published by various research groups on these fields are provided.

Traditional drug delivery systems are not efficient for peptide, protein and nucleic acid (plasmid DNA, oligonucleotides or short interfering RNA) delivery, thereby LNP have been exploited as potential delivery and targeting systems of these molecules. Since their discovery in the early 90's several research groups have focused their efforts on the improvement of this kind of nanocarriers in terms of effectiveness and safety. This review features the recent and most relevant patents related to these topics, with particular attention to targeting and protection from environmental agents. Moreover, in the case of nucleic acids strategies to improve transfection mediated by lipid nanoparticles (entrance to the cells, intracellular distribution or going through nuclear envelope) will be assessed. Regarding peptides and proteins, enhancement of encapsulation efficiency and absorption through mucoses are the main studied drawbacks. Finally, this work also includes a summary of the existing patents about the use of LNP as immune response adjuvants by using either plasmid DNA or proteins.

Design of oral fast-release solid dispersion of poorly water-soluble drugs has been a great challenge over past decades on issues of drug recrystallization, drug polymorphism, formulation limited to low drug-to-carrier ratio and drug particle aggregation in matrix. The complexity in solid dispersion design is envisaged to be resolvable by the use of nanoparticulate system as solid dosage form. This manuscript reviews several patented processing approaches of nanoparticulate solid dispersion that have been reported recently. Through drug nanoencapsulation, a higher content of drug may be delivered with less aggregation via placing the same drug mass in a greater number of tinier carriers. Nanoencapsulation, by its own process of formation, brings about submicron particles. Keeping drug in these nanoparticles, a remarkable rise in specific surface area of drug is realized for dissolution. The augmentation of drug dissolution can be sufficiently high to the extent that the influences of polymorphism and crystallization phenomenon on drug dissolution in a solid dispersion may be negligible.

High lipophilicity and high lattice energy of drugs, which result in poor solubility are major real challenges in the pharmaceutical industry for the successful development and commercialization of suitable dosage forms. Therefore various formulation strategies like complexation, lipid based systems, micronization, nanonization, co-crystals, solid dispersions, solubilization etc. have been investigated to resolve the problems associated with solubility related oral bioavailability of poorly water soluble drugs. This article focuses on solid dispersions which is used as one of the formulation strategies to improve the solubility and bioavailability of BCS class II drugs. The present review discusses the fundamentals of solid dispersions, their formulation techniques including various carriers used, their applications, limitations as well as provide an insight into the various alternative approaches to overcome problems associated with solid dispersions. This review also discusses some important aspects of solid dispersion like phase transition, importance of Tg for solid dispersion, controlled release formulations, IVIVC, and the prospect of innovative solid dispersions. Furthermore, the different patents highlighting the applications of solid dispersions have also been comprehensively discussed in the present review.

Intelligent hydrogel, also known as smart hydrogels, are materials with great potential for development in drug delivery system. Intelligent hydrogel also has the ability to perceive as a signal structure change and stimulation. The review introduces the temperature-, pH-, electric signal-, biochemical molecule-, light- and pressure- sensitive hydrogels. Finally, we described the application of intelligent hydrogel in drug delivery system and the recent patents involved for hydrogel in drug delivery.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets and therapeutic agents related to drug delivery and formulations.

We the authors (Rajeev K. Tyagi, Neeraj K. Garg, Sharad Mangal, Hemant Khambete) of the paper entitled “mucosal delivery of vaccines: role of mucoadhesive/biodegradable polymers” published in ‘recent patents on drug delivery & formulation’ 2010; 4: 114-128, volume-4, no.2 regretfully confirms that we had included the name of Pradeep K. Sharma eroneously. Please do not consider his name amongs the authors. We accept all responsibility of inclusion and deletion of his name from the paper.