Leeladhar Prajapati*et al. /International Journal Of Pharmacy&Technology ISSN: 0975-766X CODEN: IJPTFI Available through Online Review Article www.ijptonline.com LIPOSPHERES: RECENT ADVANCES IN VARIOUS DRUG DELIVERY SYSTEM

Use of lipids as commonly used excipients like emul sifiers; base for semisolid preparations such as oi ntments, creams; as flow modifiers for granule preparations in tablet m aking are known since ages in formulation technolog y. But researchers are looking at the application of lipids in drug de liv ry from a different facet. Much of research is now focused on using lipids as novel carriers for drug moieties. Lipid b ased drug delivery systems like solid lipid nanopar ticles, lipospheres (LS) are being developed as substitutes for “polymer bas ed delivery systems” due to the increasing toxicity related concerns of monomers after intracellular processing of polymers and attractive benefits offered by lipids as carri ers. This article reviews lipospheres in particular as delivery syste m. Formulation of lipospheres, factors influencing the quality attributes of lipospheres, mechanisms behind drug loading, eva luation of lipospheres and challenges in the develo pment of lipospheres are discussed in detail.LS composed of triglycerides and monoglycerides are produced by me lt dispersion technique, solvent evaporation or multiple emulsion method. The various bio active compounds are incor porated in to LS that can be administered in to various routes.


Introduction
Liposphere formulation is an aqueous micro dispersion of solid water insoluble spherical micro particles of particle size between 0.01 and 100 µm in diameter. The lipospheres are made of solid hydrophobic triglycerides with a monolayer of phospholipids embedded on the surface of the particle. Liposphere formulation is appropriate for oral, parenteral and topical drug delivery system. The solid core containing a drug dissolved or dispersed in a solid fat matrix and used as carrier for hydrophobic drugs. Several techniques, such as solvent emulsification evaporation, hot and cold homogenization and high pressure homogenization have been used for the production of lipospheres 1 . Benefits of liposphere drug delivery system are; a) Improving drug stability; b) possibility for controlled drug release; c) controlled particle size; d) high drug loading. In addition, use of lipospheres for oral administration, it can protect the drug from hydrolysis, as well as improve drug bioavailability 2 . Therefore, the present review article is focused on achievements of lipospheres formulation to deliver the drugs in the targeted sites.
Due to several limitations with polymeric delivery systems, extensive attempts are being made to develop alternate carriers. Lipids 17 especially, are now being studied widely due to their attractive properties namely physicochemical diversity, biocompatibility, biodegradability, ability to increase the oral bioavailability of poorly water soluble drug moieties, thus making them ideal candidates as carriers for problematic drugs.

Advantages of lipid based delivery systems
Physical stability of lipid dosage forms like polymorphic phase transitions of drug and Lipid based drug delivery systems like solid lipid nanoparticles (a technology owned by Skye Pharma) 18 and lipospheres are now being studied widely. Solid lipid nanoparticles [19][20] are nanosized lipid carriers in which lipidic core contain the drug in dissolved or dispersed state. These systems were designed to substitute polymeric carriers due to the inherent toxicity. Lipospheres are lipid based dispersion systems in which drug is dissolved or dispersed in lipidic core, the surface of which is embedded with emulsifier layer. Particle size of such lipid particles ranges from 0.2-100 micrometer (µm).   [26][27] Several categories of drugs like antibiotics, anti-inflammatory compounds, vasodilators, anticancer agents, proteins and peptides are being formulated as oral lipospheres.
The formulation of Lipospheres are generally composed.

Melt dispersion technique 28
In this method, drug is dissolved or dispersed in the molten lipidic phase (figure2 oil>tristearin>tricaprin>corn oil>stearic acid. Also inclusion of negatively charged lipids like dimyristoyl phosphotidyglycerol in the lipid core was found to improve the antibody response to encapsulated malaria antigen.

Solvent evaporation method 28
In this method, lipid is dissolved in an organic solvent. Commonly used organic solvents include ethyl acetate, ethanol, acetone or dichloromethane. This lipid phase is emulsified into aqueous phase containing emulsifier. Organic solvent is evaporated by stirring the oil in water emulsion for 6-8 hrs under ambient conditions. Discrete lipospheres can be collected by filtration through paper filter after the water rises to the surface. Examples of the drugs formulated as lipospheres by this method include paclitaxel 39 , thymocartin, bovine serum albumin, triptorelin leuprolide 40 .

Microemulsion 41
In this method, drug is added to the melted lipid. Aqueous phase is prepared by adding surfactant like Tween 80 into water maintained at same temperature as lipid phase. This is followed by the addition of co-surfactant like butyl alcohol to the aqueous phase. The aqueous phase containing surfactant and co-surfactant is added to lipid phase kept under stirring. Rapid cooling of the above mixture results on formation of discrete lipid particles. Flurbiprofen lipospheres 42 are prepared by this method. Presence of Tween80 at 2%, butyl alcohol at 2ml and water at 50ml found to give discrete lipospheres of superior quality.

Production of Lipospheres for bioactive compound delivery
The solvent evaporation technique is often used for liposome and polyester. Microparticles can be present in the delivery system and could result in severe acceptability and toxicity problems. The drug delivery system concept is not new. the encapsulated drug. The encouraging results obtained in this study could propose LS for future in vivo studies, especially in the delivery of anti-infective and hormone.

Lipospheres as delivery systems for peptides and proteins
Delivery systems are designed to protect an incorporated drug from the environment during delivery and to provide a controlled release. The goal may be either to deliver a drug locally to specific sites in the body or to prepare a drug carrier system that acts as a reservoir at the site of injection over a certain time period 49 In recent years, a growing number of potential peptide and protein drugs has been discovered as a result of progress in biotechnology and genetic engineering. Unfortunately, protein drugs are subject to numerous chemical and physical instability mechanisms and rapid enzymatic degradation; therefore, they often show low bioavailability and have short in vivo half-lives, thus necessitating parenteral delivery 50   Note: LHRH = luteinizing hormone-releasing hormone; L-PLA = L-poly(lactic acid); PLGA = poly(lacticco-glycolic acid); PLA = poly(lactic acid); w/o/w = water/oil/water; o/w = oil/water.

Lipospheres for vaccine delivery
The tremendous advances of genetic engineering and the ability to obtain many synthetic recombinant protein antigens

Cationic lipospheres (cls) as delivery systems for nucleic acid molecules
Gene delivery or the release of exogenous genetic material into cells or tissues at a pathological state, has recently received much attention as a therapeutic methodology for a number of acquired and inherited diseases, including cancer.
Thus, the key to success for any gene therapy strategy is to design a vector able to provide safe and efficient gene transcription of the transgene in a variety of cells and tissues. In this view, the development of protocols aimed at obtaining optimal and efficient genetic transfer has been studied 71-73 and has led to the production of many delivery vehicles that are able to bind to DNA. The optimal carrier has to accumulate at sites of diseases such as infections, inflammations, and tumors and has to be a small, neutral, and highly serum-stable particle. Moreover, it has to be not readily recognized by the fixed and free macrophages of Accordingly the free drug contents of formulations containing the long chain triglycerides were found to be lower than short chain triglycerides 77 . Also long chain triglycerides were found to increase the bioavailability of drug as they increase in gastrointestinal residence time of drug compared to medium chain and short chain fatty acids 78 Lipid excipients reduce the activity of P-glycoprotein and MDR (multi drug resistant) associated protein 2 by down regulating the protein expression and increase in cell membrane permeability in addition to lymphatic uptake.

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Type of impeller Lipospheres were produced using different impeller types 76 and particle characteristics of formed lipospheres were studied. Impellers used were of rotor (2-blade, 3-blade) type, helicoidal rotor (4-blade) type, double truncated cone rotor. Lipospheres could not be produced using 2-blade rotor and resulted in the formation of elliptical particles. The size and surface characteristics of lipospheres can be determined by methods like electron microscopy, atomic force microscopy (AFM), nuclear magnetic resonance (NMR) and acoustic methods.

Conclusion
Lipid based delivery systems like lipospheres offer new type of carrier system for lipophilic drugs. Easy availability of formulation ingredients and feasible, simple production techniques offer attractive option for formulation of lipospheres at industrial scale. Owing to the finer particle size of lipospheres and presence of a surface stabilized by emulsifier particles, bioavailability of several problematic drugs was found to increase. Recent works demonstrate sustained release of drugs entrapped in lipospheres. Hence lipospheres can be considered as new formulation approach for drug moieties.
Lipid carriers have bright future due to their inherent property to enhance the bioavailability of lipophilic drugs with poor water solubility. However, the limitations of these carriers like poor physiochemical properties of lipids, lack of drug solubility database in lipids and unavailability of standard methodologies for in-vitro analysis, need to be addressed. Liposphere formulations were effective in delivering various drugs and biological agents including: local anesthetics, antibiotics, vaccines, and anticancer agents with a prolonged activity of up to four to five days. The liposphere approach employs a fat lipid environment to achieve desired goal for controlled and safe delivery of drugs.
Lipospheres have the potential to be a major contributor to the search for better oral, parentral and topical drug delivery systems due to their improved adsorption and penetration. In addition, lipospheres could be suitable for low cost production, clinical and large-scale production. Therefore, Lipospheres could be considered as a promising delivery system for oral, parental and topical delivery of lipophilic drugs.