Lipospheres and pro-nano lipospheres for delivery of poorly water soluble compounds

https://doi.org/10.1016/j.chemphyslip.2012.01.007Get rights and content

Abstract

Lipospheres are a drug encapsulation system composed of water dispersible solid microparticles of particle size between 0.01 and 100 μm in diameter with a solid hydrophobic lipid core stabilized by a layer of phospholipid molecules embedded in their surface. The bioactive compound is dissolved or dispersed in the solid lipid matrix of the internal core. Since lipospheres were introduced in the beginning of the 1990s, they have been used for the delivery of multiple types of drugs by various routes of administration. Later, a self-assembling pro-nano lipospheres (PNL) encapsulation system was developed for oral drug delivery. Lipospheres have several advantages over other delivery systems, such as better physical stability, low cost of ingredients, ease of preparation and scale-up, high dispersibility in an aqueous medium, high entrapment of hydrophobic drugs, controlled particle size, and extended release of entrapped drug after administration, from a few hours to several days.

This review article focuses on updated information on several aspects of lipospheres and PNL, including preparation techniques, physicochemical properties and in vitro evaluation methods. Additionally, it covers lipospheres and PNL utilization for oral, ocular, and parenteral delivery, with special attention to unique considerations and aspects for each route of administration.

Highlights

► The use of in situ self assembling (pro-nano) lipospheres is a suitable strategy to enhance the oral bioavailability of lipophilic drugs. ► Lipospheres can be utilized for drug administration via oral, ocular and parenteral routes. ► Some lipospheres advantages are: high stability and dispersibility, controlled particle size, high drug entrapment and extended release. ► The review focuses on preparation, physicochemical properties, in vitro evaluation and biopharmaceutical properties of lipospheres and PNL.

Introduction

The introduction of combinatorial chemistry accompanied by advances in in vitro high throughput screening methods has resulted in the rapid identification of many highly potent but poorly water soluble drug candidates. In fact, to date, more than 40% of new chemical entities are lipophilic and exhibit poor water solubility (Lipinski et al., 2001). Development of such poorly water soluble compounds towards clinically available drugs presents a great challenge facing the pharmaceutical scientists. Consequently, the understanding that the development of new active compounds alone is not enough to guarantee adequate pharmacotherapy of various disease states became widely accepted. Promising results obtained in in vitro studies very often are not corroborated by successful in vivo data. Multiple reasons stand behind these in vivo results. Some drugs do not reach sufficient plasma concentrations due to limited solubility, poor absorption and extensive first pass metabolism. Some are characterized by unpredictable fluctuations in plasma drug levels and thus lack effective dose–response correlation. Poor water solubility might exclude the possibility for IV administration as well. Other drugs are distributed to additional tissues besides the site of action and cause harsh adverse effects or toxicity. Toxicity and lack of therapeutic effect might also result from a drug's decomposition during its voyage from the intestinal lumen to the systemic blood circulation.

A promising strategy to overcome these obstacles is the development of suitable drug delivery systems (DDS). The understanding that the in vivo fate of the drug is dictated not only by the drug itself, but also by the mode of administration and the carrier system which should enable an optimal drug release profile according to the therapy requirements is crucial for such development (Mehnert and Mader, 2001). One of the most popular pharmaceutical approaches to overcome these obstacles is the use of various nano-dispersion systems as carriers of drug substances.

Though the concept of the essential scientific field of modern times – nanotechnology – was introduced in 1959 by Feynman in his famous lecture “There's plenty room at the bottom”, the primary development of nanotechnology occurred only in the nineteen eighties and the early nineties. The invention of the scanning tunneling microscope (STM) by Binnig and Rohrer is considered by some to be the actual beginning in the development of nanotechnologies. There are many variations of the definition of the term “nanotechnology” according to the field in which nanotechnology is applied. The US National Science Foundation defined nanotechnology as science, engineering, and technology conducted at the nano-scale of approximately 1–100 nm.

The application of nanotechnology in drug delivery systems is a very popular approach in the pharmaceutical industry to improve the bioavailability of drugs. There are a number of areas in which nanotechnology is being applied in drug delivery, e.g. improving the bioavailability of poorly water soluble drugs (Hu et al., 2004, Li et al., 2009, Zhang et al., 2011, Manjunath and Venkateswarlu, 2006), drug targeting i.e. transporting therapeutic agents to a specific cell or tissue (Wong et al., 2007) and controlled release delivery systems (Yang et al., 1999, zur Muhlen et al., 1998).

Lipospheres are lipid-based water dispersible solid particles of particle size between 0.01 and 100 μm in diameter composed of a solid hydrophobic lipid core (triglycerides), stabilized by a layer of phospholipid molecules embedded in their surface. The lipospheres are suitable for oral, parenteral and topical drug delivery of bioactive compounds and are designed to overcome the drawbacks associated with traditional colloidal systems such as emulsions, liposomes and polymeric nanoparticles (Domb et al., 1996, Maniar et al., 1991).

The internal core contains the bioactive compound dissolved or dispersed in the solid fat matrix (Bekerman et al., 2004).Various lipospheres have been used for the controlled delivery of different types of drugs including anti-inflammatory compounds, local anesthetics, antibiotics, and anticancer agents, as well as carriers of vaccines and adjuvants (Domb, 2006, Amselem, 1996, Amselem et al., 1992b, Amselem et al., 1992a).

Similar systems based on solid fats and phospholipids have been described, as well as solid lipid nanospheres (SLN) which are essentially nano-size lipospheres. All of the above were extensively reviewed elsewhere (Domb, 2006, Muller et al., 2000).

Passive and active targeting of nano-lipospheres is also possible based on two different approaches. Firstly, nano-lipospheres would be able to deliver a concentrated dose of drug in the vicinity of the tumor via the enhanced permeability (passive targeting) and retention effect. Secondly, active targeting to various tissues may be achieved via utilization of ligands on the surface of nanoparticles. In addition, nano-lipospheres would reduce the drug's presence in healthy tissues by limiting drug distribution to the target organ (Irache et al., 2011). The broad subject of targeting, and especially active and carrier mediated targeting of nanoparticles is beyond the scope of this review and is extensively reviewed elsewhere (Peer et al., 2007, Chrastina et al., 2011, Shapira et al., in press).

Lipospheres have several advantages over other particulate delivery systems such as emulsions, liposomes and microspheres, including: improved drug stability, formulation stability, the ability to freeze dry and reconstitute, the possibility for controlled drug release, high drug payload, controlled particle size and the avoidance of carrier toxicity and the presence of organic solvents. Advantages of the use of lipospheres for oral administration include the possibility for drug protection from hydrolysis, as well as increased drug bioavailability and prolonged plasma levels (Souto and Muller, 2007). In addition, the matrix is composed of physiological components and/or excipients of accepted status (e.g. GRAS status), which reduces the risk for acute/chronic toxicity (Domb, 2006). On the other hand, the disadvantages of such delivery systems are associated mostly with their preparation techniques involving high pressure and rapid temperature changes, and include high pressure induced drug degradation, lipid crystallization, gelation phenomena and co-existence of several colloidal species (Mehnert and Mader, 2001). Today, several techniques are employed to produce lipospheres, such as high pressure homogenization, hot and cold homogenization, solvent emulsification evaporation, etc. (Souto and Muller, 2007). An alternative method is in situ preparation of lipospheres with a particle size below 100 nm. This method was developed by using a dispersible pre-concentrate system (Bekerman et al., 2004). This delivery system, termed pro-nano liposphere (PNL), is based on a solution containing the drug, triglyceride, phospholipid and other additives in a mixture of common surfactants, and an organic solvent that is miscible with all components. This solution spontaneously forms nanoparticles when gently mixed in an aqueous media, such as the upper GI lumen content.

This review will focus on updated information on the preparation, physicochemical properties and in vitro evaluation of lipospheres and PNL as carrier systems for poor water-soluble drugs. These lipid dispersions can be used for different routes of administration. The peroral route is the most preferred mode of drug administration and the parenteral route is the most challenging one. Thus, the center of attention of this review will be nano-dispersion systems for parenteral and peroral administration of poor water-soluble compounds. Nevertheless, ocular and CNS-targeted administrations will be discussed as well.

Section snippets

Preparation of lipospheres and PNL

The internal hydrophobic core of lipospheres is composed of lipids, mainly solid triglycerides, while the surface activity of liposphere particles is provided by the surrounding phospholipid layer. The clear advantage of lipospheres is the fact that the lipid core consists of physiological naturally occurring biodegradable lipids, thus minimizing the danger of acute and chronic toxicity.

The lipid that constitutes the core component of the lipospheres and PNL is solid at room temperature, and

In vitro characterization of lipospheres and PNL

Proper characterization of lipospheres and PNL is a serious challenge due to the colloidal size of the particles and the complexity and dynamic nature of the delivery system (Mukherjee et al., 2009). The most important parameters which need to be evaluated are discussed below:

Oral delivery

The majority (∼85%) of the 50 most-sold pharmaceutical products in the North American and European markets are given orally. This route is the most preferred mode of drug administration presently because of its safety, comfort, low economic burden and improved patient medication adherence in comparison to alternative administration routes such as intramuscular, subcutaneous, rectal or pulmonary drug delivery (Lennernas et al., 2007). The introduction of combinatorial chemistry accompanied by

Current status of lipospheres and PNL's in research and clinic

During the past two decades the potential of utilizing lipid-based dispersion systems as efficient drug carriers for different administration routes have been recognized by many researchers and have been extensively studied both in vitro and in vivo in the attempt to develop commercial products. However, despite the attractive advantages attributed to lipid dispersion systems and immense efforts put into research, currently, there are only a few commercially available systems based on solid

Summary and future perspectives

The rapidly growing pharmaceutical industry is strongly focused on the development of new active molecules. However, a successful delivery system is not of less importance to assure the progress of a new chemical entity from the preclinical to clinical development stage, and ultimately to the market. The drug delivery system should enable therapeutic drug concentrations at the drug target site for a sufficient time period, and avoid the occurrence of as many adverse effects in other tissues and

Acknowledgments

The authors would like to thank Dr. Wahid Khan for his excellent assistance. Prof. A.J. Domd and Prof. A. Hoffman are affiliated with the David R Bloom Center of Pharmacy.

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