**7. New generation liposomes**

Liposomes made up of commonly used ester phospholipids such as phosphatidylcholine are referred as conventional liposomes. These structures are very attractive for encapsulation and drug delivery applications to entrap both hydrophilic and hydrophobic materials due to the presence of aqueous core part as well as the lipid bilayer. Up to this date, there are many formulations in the market and also in the clinical trials. However, none of them truly overcome their chemical and physical instability problems especially during the transfer to the site of action [120]. Various attempts like modification of the liposome surface with i.e. hydrophilic polyethylene glycol polymers, using cryoprotectants or incorporation of high amount of cholesterol into the bilayer have led to only limited success. Other than instability problems, liposomal drug vehicles show extensive leakage of water-soluble drugs during the passage through the gastrointestinal tract and they are heterogeneous in terms of size distribution. Therefore, scientists have been looking for new drug delivery formulations that could address these issues about liposomes, which lead to the so-called new generation of liposomes which will be summarized in this section.

Archaeosomes are liposomal formulations that are prepared with one or more lipids, mainly containing diether and/or tetraether linkages, found in archaeobacterial membrane [165]. These archaeobacterial lipids present unique features and higher stabilities to several conditions (high or low temperatures, high salinity, acidic media, anaerobic atmosphere, high pressure) over conventional liposomes [166]. The definition of archaeosomes also includes the use of synthetically derived lipids that have the properties of archaeobacteri‐ al ether lipids, that is, regularly branched phytanyl chains attached via ether bonds at sn-2,3 glycerol carbons [167]. The surprising stability of archaeosomes can be attributed to some properties brought by the archaeobacterial lipids' structure: (i) the ether linkages that are more stable than esters over a wide range of pH, and the branching methyl groups help both to reduce crystallization and permeability; (2) the stability towards oxidative degrada‐ tion of these lipid membranes are provided by the fully saturated alkyl chains in the archaeobacterial lipids; (3) the unusual stereochemistry of the glycerol backbone ensures the resistance of the membrane to enzymatic attack; (4) the bipolar lipids span the membranes and enhance their stability properties [167, 168].

Archaeosomes can be prepared by using conventional procedures (hydration of a thin film followed by sonication or extrusion, detergent dialysis) at any temperature in the physiolog‐ ical range or lower, thus making it possible to encapsulate thermally labile compounds. Additionally, they can be prepared and stored in the presence oxygen without any degradation. According to the clinical experiments, in vivo and in vitro, these new drug delivery vehicles are not toxic. Thus, the biocompatibility and better stability of archaeo‐ somes in numerous conditions offer advantages over conventional liposomes for their usage in biotechnology including vaccine and drug/gene delivery [167]. Consequently, they can be considered as better carriers than conventional liposomes, especially for protein and peptide delivery due to their high stability. Li et al. showed the superiority of archaeo‐ somes over conventional liposomes in their study in which they used insulin as a model peptide for its oral delivery [169].

have also shown antitumor effect in Taxol-resistant tumor models [164]. Abraxane®, the only nonliposomal preparation of PTX, (albumin nanoparticle-based PTX preparation) and Lipusu® (liposomal PTX approved by State FDA of China) have entered the field of clinical applications. LEP-ETU (NeoPharm) and EndoTAG®-1 (Medigene) have reached the phase II of the clinical trials. Generally, liposomes and protein nanoparticles represent a promising approach to the optimization of PTX delivery. Their commercialization is at the doorstep of

Liposomes made up of commonly used ester phospholipids such as phosphatidylcholine are referred as conventional liposomes. These structures are very attractive for encapsulation and drug delivery applications to entrap both hydrophilic and hydrophobic materials due to the presence of aqueous core part as well as the lipid bilayer. Up to this date, there are many formulations in the market and also in the clinical trials. However, none of them truly overcome their chemical and physical instability problems especially during the transfer to the site of action [120]. Various attempts like modification of the liposome surface with i.e. hydrophilic polyethylene glycol polymers, using cryoprotectants or incorporation of high amount of cholesterol into the bilayer have led to only limited success. Other than instability problems, liposomal drug vehicles show extensive leakage of water-soluble drugs during the passage through the gastrointestinal tract and they are heterogeneous in terms of size distribution. Therefore, scientists have been looking for new drug delivery formulations that could address these issues about liposomes, which lead to the so-called new generation of liposomes which

Archaeosomes are liposomal formulations that are prepared with one or more lipids, mainly containing diether and/or tetraether linkages, found in archaeobacterial membrane [165]. These archaeobacterial lipids present unique features and higher stabilities to several conditions (high or low temperatures, high salinity, acidic media, anaerobic atmosphere, high pressure) over conventional liposomes [166]. The definition of archaeosomes also includes the use of synthetically derived lipids that have the properties of archaeobacteri‐ al ether lipids, that is, regularly branched phytanyl chains attached via ether bonds at sn-2,3 glycerol carbons [167]. The surprising stability of archaeosomes can be attributed to some properties brought by the archaeobacterial lipids' structure: (i) the ether linkages that are more stable than esters over a wide range of pH, and the branching methyl groups help both to reduce crystallization and permeability; (2) the stability towards oxidative degrada‐ tion of these lipid membranes are provided by the fully saturated alkyl chains in the archaeobacterial lipids; (3) the unusual stereochemistry of the glycerol backbone ensures the resistance of the membrane to enzymatic attack; (4) the bipolar lipids span the

Archaeosomes can be prepared by using conventional procedures (hydration of a thin film followed by sonication or extrusion, detergent dialysis) at any temperature in the physiolog‐

modern drug delivery market.

24 Application of Nanotechnology in Drug Delivery

**7. New generation liposomes**

will be summarized in this section.

membranes and enhance their stability properties [167, 168].

Another development aiming to enhance tissue targeting is virosomes in which the liposome surface is modified with fusogenic viral envelope proteins [170]. Virosomes have been used for the intracellular delivery of drugs and DNA [171, 172] as well as the basis of the newly developed vaccines which are very effective in the delivery of protein antigens to the immune system [173]. As a result, a whole set of virosomes-based vaccines have been developed for human and animal use. Special attention has been paid to the delivery of influenza vaccine using virosomes containing the spike proteins of influenza virus. Virosome-based vaccines were found to be highly immunogenic and well tolerated in children. A similar approach was used to prepare virosomal hepatitis A vaccine that elicited high antibody titres after primary and booster vaccination of infants and young children which was also confirmed for the healthy adults and elderly patients [174-176]. In general, virosomes can provide an excellent opportunity for the efficient delivery of both various antigens and many drugs, including nucleic acids, cytotoxic drugs and toxoids [177, 178], although they might present certain problems associated with their stability, leakiness and immunogenicity.

Niosomes, exhibiting a similar behavior to liposomes, are the vesicles that are made up of nonionic surfactants (e.g. alkyl ethers and alkyl esters) and cholesterol. These structures are stable on their own and they increase the stability of the encapsulated drugs. No special conditions are needed for handling and storage of these surfactants. Niosomes improve the oral bioavailability of poorly absorbed drugs, and enhance skin penetration of drug. When compared with liposomes, their oral absorption is better due to the replacement of phospho‐ lipids with nonionic surfactants which are less susceptible to the action of bile salts, parenteral, as well as topical routes. These delivery systems are biodegradable, biocompatible and nonimmunogenic. Niosomes improve the therapeutic performance of drug molecules by delaying the clearance from the circulation and protecting the drug from biological environment [179].

The transdermal delivery is one of the most important routes of drug administration. The main factor which limits the application of transdermal route for drug delivery is the permeation of drugs through the skin. Human skin has selective permeability for drugs. Lipophilic drugs can pass through the skin but the drugs which are hydrophilic in nature can not pass through. Water soluble drugs either show less or no permeation. To improve the permeation of drugs through the skin various mechanisms have been investigated, including use of chemical or physical enhancers, such as iontophoresis, sonophoresis, etc. Liposomes and niosomes are not suitable for transdermal delivery due to poor skin permeability, breaking of the system, aggregation, drug leakage, and fusion of vesicles [180].

delivery of pharmaceuticals and cosmeceuticals by utilizing non-phospholipid structures. Various FDA-regulated products such as human pharmaceuticals and vaccines can be developed by this technology [205, 206]. These nonionic vesicles composed of glyceryl dilaurate with cholesterol and polyoxyethylene-10-stearyl ether have been known to deliver greater amounts of cyclosporine into and through hairless mouse skin than phosphatidyl choline or ceramide based vesicles [206]. Among various liposomal formulations, novasomes appeared more effective when delivered under non-occluded conditions from a finite dose [206]. Various vaccines based on novasomes have been licensed for the immunization of fowl against Newcastle disease virus and avian rheovirus [135]. Some of the novasome-based vaccines against bacterial and viral infections have been developed such as small pox vaccine while still many are under development [207]. Novasomes inactivate viruses such as ortho‐ myxoviruses, paramyxoviruses, coronaviruses and retroviruses, etc., by fusing with envel‐ oped virus and that the nucleic acid of the virus denatures shortly after the fusion [208].

Liposomes as Potential Drug Carrier Systems for Drug Delivery

http://dx.doi.org/10.5772/58459

27

Although liposomes are like biomembranes, they are still foreign objects of the body. There‐ fore, liposomes are known by the mononuclear phagocytic system (MPS) after contact with plasma proteins. Accordingly, liposomes are cleared from the blood stream. For more than two decades, various PEG derivatives have been used to stabilize for increasing efficiency in drug or gene delivery. Most 'stabilized' liposomes, the so-called stealth liposomes [78], or cryptosomes [84], contain a certain percentage of PEG-derivatized phospholipids, which reduce the uptake by MPS, thereof prolonging the circulation times and making available abundant time for these liposomes to leak from the circulation through the leaky endothelium. Unlike, conventional liposomes, PEG-liposomes do not show dose dependent blood clearance kinetics [209]. Vesicles containing PEG-conjugated lipids at various concentrations, molecular weights, or various sizes of PEG-containing vesicles were reported to have different circulation times [81, 84, 210-212]. These kind of liposomal systems are generally used in the ligandmediated drug targeting [213]. This stealth principle has been used to develop the successful doxorubicin-loaded liposome product that is presently available in the market as Doxil (Janssen Biotech, Inc., Horsham, USA) or Caelyx (Schering-Plough Corporation, Kenilworth,

Cryptosomes is a liposomal composition for targeted delivery of drugs. The composition comprises poloxamer molecules and liposomes encapsulating one or more delivery agents. Poloxamers are polyethylene oxide (PEO)-polypropylene oxide (PPO)-polyethylene oxide triblock co-polymers of different molecular weights. The hydrophobic PPO group in the middle links the two hydrophilic PEO groups. The hydrophilic PEO groups of a poloxamer, on either side of the central PPO unit, can provide steric protection to a bilayer surface. The amphiphilic nature of the poloxamers makes them extremely useful in various applications as emulsifiers and stabilizers. It is considered that the central PPO unit, being hydrophobic, would tend to push into the bilayer interior serving as an anchor. Dislodging the poloxamer molecule from the bilayer is achieved by reducing its hydrophobicity which is achieved by decreasing the temperature. In an aqueous medium, poloxamers stay as individual molecules at temperatures below their critical micelle temperature (CMT), but at temperatures above the CMT, they form micelles due to their amphiphilic nature. In the presence of lipid bilayers, some poloxamer

USA) for the treatment of solid tumors.

A new type of carrier system, suitable for transdermal delivery, called transfersome has been proposed for the delivery of proteins and peptides like insulin, bovin, serum albumin, vaccines, etc. These systems are soft and malleable carriers that offer noninvasive delivery of drug into or across the deeper skin layers and/or the systemic circulation [181]. Transfersomes improve the site specificity while providing the safety of the drug. Transfersomes are the lipid supra‐ molecular aggregates which make them very flexible. This flexibility as well as their good penetration ability causes them to be used in the effective delivery of non-steroidal antiinflammatory agents like ibuprofen and diclofenac [182].

Alternatively, unlike classic liposomes [183, 184], that are known mainly to deliver drugs to the outer layers of skin, ethosomes can enhance permeation through the stratum corneum barrier [185-187]. Ethosomes, developed by Touitou in 1997, are the slight modification of well established drug carrier liposome, containing phospholipids, alcohol (ethanol or isopropyl alcohol) in relatively high concentration and water [188]. The size of these soft vesicles can vary from nanometers to microns [189-193]. The high concentration of ethanol makes the ethosomes unique. The ethanol in ethosomes causes disturbance in the skin lipid bilayer organization, hence when incorporated into a vesicle membrane, it enhances the vesicle's ability to penetrate the stratum corneum. Also, because of the high concentration of ethanol the lipid membrane is packed less tightly than conventional vesicles but has equivalent stability, allowing a more malleable structure and improves drug distribution ability in stratum corneum lipids. Ethosomes can be used for many purposes in drug delivery for the treatment of many diseases such as Minoxidil for baldness, testosterone as steroidal hormone, Trihexyphenidyl hydrochloride for Parkinson's disease, Zidovudine and Lamivudine as anti-HIV, Bacitracin as antibacterial, Erythromycin as antimicrobial, DNA for genetic disorders, Cannabidol in the treatment of rheumatoid arthiritis and many others [190, 192, 194-201].

Novasomes are the modified forms of liposomes [202] or a type of niosomes prepared from the mixture of monoester of polyoxyethylene fatty acids, cholesterol and free fatty acids with the diameter of 0.1-1.0 microns. They consist of two to seven bilayer shells that surround an unstructured space occupied by a large amorphous core of hydrophilic or hydrophobic materials [203]. The inner amorphous core can be loaded up to 80-85% with a medical drug and the surfaces of novasomes can be positive, negative or neutral.

Novasomes offer several advantages to the owners of the product such as: Both hydrophil‐ ic and hydrophobic products can be incorporated in the same formulation, drugs show‐ ing interactions can be incorporated in between bilayers to prevent incompatibility, they can be made site specific due to their surface charge characteristics, they can deliver a large volume of active ingredient, thus also reducing the frequency of application, and they have the ability of adhering skin or hair shafts which makes novasomes applicable in the cosmetic formulations [204].

Novasomes have extensive utilization in fields of foods, cosmetics, personal care, chemical, agrochemical and pharmaceuticals. The technology enhances absorption rate via topical delivery of pharmaceuticals and cosmeceuticals by utilizing non-phospholipid structures. Various FDA-regulated products such as human pharmaceuticals and vaccines can be developed by this technology [205, 206]. These nonionic vesicles composed of glyceryl dilaurate with cholesterol and polyoxyethylene-10-stearyl ether have been known to deliver greater amounts of cyclosporine into and through hairless mouse skin than phosphatidyl choline or ceramide based vesicles [206]. Among various liposomal formulations, novasomes appeared more effective when delivered under non-occluded conditions from a finite dose [206]. Various vaccines based on novasomes have been licensed for the immunization of fowl against Newcastle disease virus and avian rheovirus [135]. Some of the novasome-based vaccines against bacterial and viral infections have been developed such as small pox vaccine while still many are under development [207]. Novasomes inactivate viruses such as ortho‐ myxoviruses, paramyxoviruses, coronaviruses and retroviruses, etc., by fusing with envel‐ oped virus and that the nucleic acid of the virus denatures shortly after the fusion [208].

suitable for transdermal delivery due to poor skin permeability, breaking of the system,

A new type of carrier system, suitable for transdermal delivery, called transfersome has been proposed for the delivery of proteins and peptides like insulin, bovin, serum albumin, vaccines, etc. These systems are soft and malleable carriers that offer noninvasive delivery of drug into or across the deeper skin layers and/or the systemic circulation [181]. Transfersomes improve the site specificity while providing the safety of the drug. Transfersomes are the lipid supra‐ molecular aggregates which make them very flexible. This flexibility as well as their good penetration ability causes them to be used in the effective delivery of non-steroidal anti-

Alternatively, unlike classic liposomes [183, 184], that are known mainly to deliver drugs to the outer layers of skin, ethosomes can enhance permeation through the stratum corneum barrier [185-187]. Ethosomes, developed by Touitou in 1997, are the slight modification of well established drug carrier liposome, containing phospholipids, alcohol (ethanol or isopropyl alcohol) in relatively high concentration and water [188]. The size of these soft vesicles can vary from nanometers to microns [189-193]. The high concentration of ethanol makes the ethosomes unique. The ethanol in ethosomes causes disturbance in the skin lipid bilayer organization, hence when incorporated into a vesicle membrane, it enhances the vesicle's ability to penetrate the stratum corneum. Also, because of the high concentration of ethanol the lipid membrane is packed less tightly than conventional vesicles but has equivalent stability, allowing a more malleable structure and improves drug distribution ability in stratum corneum lipids. Ethosomes can be used for many purposes in drug delivery for the treatment of many diseases such as Minoxidil for baldness, testosterone as steroidal hormone, Trihexyphenidyl hydrochloride for Parkinson's disease, Zidovudine and Lamivudine as anti-HIV, Bacitracin as antibacterial, Erythromycin as antimicrobial, DNA for genetic disorders, Cannabidol in the treatment of rheumatoid arthiritis and many others [190, 192, 194-201].

Novasomes are the modified forms of liposomes [202] or a type of niosomes prepared from the mixture of monoester of polyoxyethylene fatty acids, cholesterol and free fatty acids with the diameter of 0.1-1.0 microns. They consist of two to seven bilayer shells that surround an unstructured space occupied by a large amorphous core of hydrophilic or hydrophobic materials [203]. The inner amorphous core can be loaded up to 80-85% with a medical drug

Novasomes offer several advantages to the owners of the product such as: Both hydrophil‐ ic and hydrophobic products can be incorporated in the same formulation, drugs show‐ ing interactions can be incorporated in between bilayers to prevent incompatibility, they can be made site specific due to their surface charge characteristics, they can deliver a large volume of active ingredient, thus also reducing the frequency of application, and they have the ability of adhering skin or hair shafts which makes novasomes applicable in the cosmetic

Novasomes have extensive utilization in fields of foods, cosmetics, personal care, chemical, agrochemical and pharmaceuticals. The technology enhances absorption rate via topical

and the surfaces of novasomes can be positive, negative or neutral.

formulations [204].

aggregation, drug leakage, and fusion of vesicles [180].

26 Application of Nanotechnology in Drug Delivery

inflammatory agents like ibuprofen and diclofenac [182].

Although liposomes are like biomembranes, they are still foreign objects of the body. There‐ fore, liposomes are known by the mononuclear phagocytic system (MPS) after contact with plasma proteins. Accordingly, liposomes are cleared from the blood stream. For more than two decades, various PEG derivatives have been used to stabilize for increasing efficiency in drug or gene delivery. Most 'stabilized' liposomes, the so-called stealth liposomes [78], or cryptosomes [84], contain a certain percentage of PEG-derivatized phospholipids, which reduce the uptake by MPS, thereof prolonging the circulation times and making available abundant time for these liposomes to leak from the circulation through the leaky endothelium. Unlike, conventional liposomes, PEG-liposomes do not show dose dependent blood clearance kinetics [209]. Vesicles containing PEG-conjugated lipids at various concentrations, molecular weights, or various sizes of PEG-containing vesicles were reported to have different circulation times [81, 84, 210-212]. These kind of liposomal systems are generally used in the ligandmediated drug targeting [213]. This stealth principle has been used to develop the successful doxorubicin-loaded liposome product that is presently available in the market as Doxil (Janssen Biotech, Inc., Horsham, USA) or Caelyx (Schering-Plough Corporation, Kenilworth, USA) for the treatment of solid tumors.

Cryptosomes is a liposomal composition for targeted delivery of drugs. The composition comprises poloxamer molecules and liposomes encapsulating one or more delivery agents. Poloxamers are polyethylene oxide (PEO)-polypropylene oxide (PPO)-polyethylene oxide triblock co-polymers of different molecular weights. The hydrophobic PPO group in the middle links the two hydrophilic PEO groups. The hydrophilic PEO groups of a poloxamer, on either side of the central PPO unit, can provide steric protection to a bilayer surface. The amphiphilic nature of the poloxamers makes them extremely useful in various applications as emulsifiers and stabilizers. It is considered that the central PPO unit, being hydrophobic, would tend to push into the bilayer interior serving as an anchor. Dislodging the poloxamer molecule from the bilayer is achieved by reducing its hydrophobicity which is achieved by decreasing the temperature. In an aqueous medium, poloxamers stay as individual molecules at temperatures below their critical micelle temperature (CMT), but at temperatures above the CMT, they form micelles due to their amphiphilic nature. In the presence of lipid bilayers, some poloxamer molecules would partition into the bilayers as well as forming micelles with other poloxamer units. If the temperature again goes below the CMT, the poloxamer molecules lose their amphiphilic nature and disassociate from the lipid bilayer or micelle [179].

The most important advantage of emulsomes is their ability to protect the encapsulated drug from harsh gastric environment of stomach before oral administration because the drug is inside the triglyceride lipid core which can be supported that the gastric pH and the gastric enzymes are unable to hydrolyze triglycerides. Also, they resist development of multi drug resistance, often associated with over expression of a cell membrane glycoprotein, which cause efflux of the drug from the cytoplasm and results in an ineffective drug concentration inside

Liposomes as Potential Drug Carrier Systems for Drug Delivery

http://dx.doi.org/10.5772/58459

29

The development of emulsomes, however, is still largely empirical, and in vitro models that are predictive of oral bioavailability enhancement are lacking. There is a need for in vitro methods for predicting the dynamic changes involving the drug in the gut in order to monitor the solubilization state of the drug in vivo. Attention also needs to be paid to the interactions between lipid systems and the pharmacologically active substance. The characteristics of various lipid formulations also need to be understood, so that guidelines can be established that allow identification of suitable candidate formulations at an early stage. Future research should involve human bioavailability studies as well as more basic studies on the mechanisms

Unilamellar vesicles or liposomes are commonly used as simple cell models and as drug delivery vehicles to follow the release kinetics of lipophilic drugs that require compartmental models in its therapeutics and triggers. The localization of the drug at the site of action, rate of achieving the therapeutic index and circulation lifetime are the key parameters for a liposome. Lately, their arises a need for a multi-compartment structure consisting of drugloaded liposomes encapsulated within another bilayer, is a promising drug carrier with better retention and stability due to prevention enzymes or proteins reaching the interior bilayers. A vesosome is a more or less heterogeneous, aggregated, large lipid bilayer enclosing multiple, smaller liposomes that offer a second barrier of protection for interior compartments and can also serve as the anchor for active targeting components [226, 76]. The multi-compartment structure of vesosome can also allow for independent optimization of the interior compart‐ ments and exterior bilayer; however, just the bilayer-within-a-bilayer structure of the veso‐

In nature, eukaryotes increased their ability to optimize their response to their surroundings by developing multiple compartments, each of which has a distinct bilayer membrane, usually of quite varied composition and physical structure. Mimicking this natural progression to nested bilayer compartments led to the development of the vesosome, or vesicles deliberately trapped within another vesicle. The vesosome has distinct inner compartments separated from the external membrane; each compartment can encapsulate different materials and have different bilayer compositions. In addition, while it has proven difficult to encapsulate anything larger than molecular solutions within lipid bilayers by conventional vesicle selfassembly, the vesosome construction process lends itself to trapping colloidal particles and biological macromolecules relatively efficiently [229, 230]. The nested bilayer compartments of the vesosome provide a degree of freedom for optimization not possible with a single membrane enclosed compartment and a more realistic approximation of higher order biolog‐

some is sufficient to increase drug retention from minutes to hours [227, 228].

of action of this fascinating and diverse group of formulations.

the cellular compartment [225].

ical organization.

Emulsome, having the characteristics of both liposomes and emulsions, is a novel lipoidal vesicular system with an internal solid fat core surrounded by phospholipid bilayer. Emul‐ somes comprise a hydrophobic core (composed of solid fates instead of oils) as in standard oilin-water emulsions, but the core is surrounded and stabilized by one or more envelopes of phospholipid bilayers as in liposomes allowing water insoluble drugs in the solution form without requiring any surface active agent or co-solvent. Emulsomes differ from liposomes since their internal core is a lipid, whereas the internal core in liposomes is an aqueous compartment. The drug loading is generally followed by sonication to produce emulsomes of smaller size [214]. These systems are often prepared by melt expression or emulsion solvent diffusive extraction. The lipid assembly of emulsomes, stabilized by cholesterol and soya lecithin (5-10% by weight), has features that are intermediate between liposomes and oil-inwater emulsions droplets. Emulsomes provide the advantages of improved hydrophobic drug loading in the internal solid lipid core and the ability of encapsulating water-soluble medica‐ ments in the aqueous compartments of surrounding phospholipid layers.

Beside the other vesicular formulations, emulsomes are much stabilized and nano range vesicles. It is a new emerging delivery system and therefore could play a fundamental function in the effective treatment of life-threatening viral infections and fungal infections such as hepatitis, HIV, Epstein-Barr virus, leishmaniasis, etc. appear promising for the treatment of visceral leishmaniasis specifically and hepato-splenic candidiasis [214-216]. Emulsomes could be utilized in order to improve oral controlled delivery of drug, vaccine, and biomacromole‐ cules. It is due to the fact that they are nano sized in range and could be utilized for the intravenous route. The common application areas of emulsomes are drug targeting, antineoplastic treatment, leishmaniasis (a disease in which a parasite of the genus Leishmania invades the cells of the liver and spleen) treatment, and biotechnology. Moreover, emulsomes could represent a more economical alternative to current commercial lipid formulations for the treatment of viral infections and fungal infections. Emulsomes provide a controlled and sustain release of drug. In comparison to the liposomes, emulsomes provide a prolong release of drug up to 24 hours, whereas liposomes have shown release up to 6 hours [217-219]. Emulsomes are nano size range in comparison to other vesicular delivery system such as niosomes and ethosomes. Due to the reduced size (10-250 nm) they can be used to enhance bioavailability to drug and as the best carrier for the intravenous drug delivery as well as oral drug delivery.

The lipid core of emulsomes may contain one or more anti-oxidants which are generally αtocopherol or its derivatives that are the members of Vitamin-E family. The presence of antioxidants reduces the formation of oxidative degradation products of unsaturated lipids such as peroxides. The need of anti-oxidant can be prevented by the usage of saturated fatty acids during the preparation of the lipid core [220]. In the formation of emulsomes, like in the case of liposomes, cholesterol is essential component for the system that influences the stability of emulsomal systems and plays an important role in the drug encapsulation [221-224].

The most important advantage of emulsomes is their ability to protect the encapsulated drug from harsh gastric environment of stomach before oral administration because the drug is inside the triglyceride lipid core which can be supported that the gastric pH and the gastric enzymes are unable to hydrolyze triglycerides. Also, they resist development of multi drug resistance, often associated with over expression of a cell membrane glycoprotein, which cause efflux of the drug from the cytoplasm and results in an ineffective drug concentration inside the cellular compartment [225].

molecules would partition into the bilayers as well as forming micelles with other poloxamer units. If the temperature again goes below the CMT, the poloxamer molecules lose their

Emulsome, having the characteristics of both liposomes and emulsions, is a novel lipoidal vesicular system with an internal solid fat core surrounded by phospholipid bilayer. Emul‐ somes comprise a hydrophobic core (composed of solid fates instead of oils) as in standard oilin-water emulsions, but the core is surrounded and stabilized by one or more envelopes of phospholipid bilayers as in liposomes allowing water insoluble drugs in the solution form without requiring any surface active agent or co-solvent. Emulsomes differ from liposomes since their internal core is a lipid, whereas the internal core in liposomes is an aqueous compartment. The drug loading is generally followed by sonication to produce emulsomes of smaller size [214]. These systems are often prepared by melt expression or emulsion solvent diffusive extraction. The lipid assembly of emulsomes, stabilized by cholesterol and soya lecithin (5-10% by weight), has features that are intermediate between liposomes and oil-inwater emulsions droplets. Emulsomes provide the advantages of improved hydrophobic drug loading in the internal solid lipid core and the ability of encapsulating water-soluble medica‐

Beside the other vesicular formulations, emulsomes are much stabilized and nano range vesicles. It is a new emerging delivery system and therefore could play a fundamental function in the effective treatment of life-threatening viral infections and fungal infections such as hepatitis, HIV, Epstein-Barr virus, leishmaniasis, etc. appear promising for the treatment of visceral leishmaniasis specifically and hepato-splenic candidiasis [214-216]. Emulsomes could be utilized in order to improve oral controlled delivery of drug, vaccine, and biomacromole‐ cules. It is due to the fact that they are nano sized in range and could be utilized for the intravenous route. The common application areas of emulsomes are drug targeting, antineoplastic treatment, leishmaniasis (a disease in which a parasite of the genus Leishmania invades the cells of the liver and spleen) treatment, and biotechnology. Moreover, emulsomes could represent a more economical alternative to current commercial lipid formulations for the treatment of viral infections and fungal infections. Emulsomes provide a controlled and sustain release of drug. In comparison to the liposomes, emulsomes provide a prolong release of drug up to 24 hours, whereas liposomes have shown release up to 6 hours [217-219]. Emulsomes are nano size range in comparison to other vesicular delivery system such as niosomes and ethosomes. Due to the reduced size (10-250 nm) they can be used to enhance bioavailability to drug and as the best carrier for the intravenous drug delivery as well as oral

The lipid core of emulsomes may contain one or more anti-oxidants which are generally αtocopherol or its derivatives that are the members of Vitamin-E family. The presence of antioxidants reduces the formation of oxidative degradation products of unsaturated lipids such as peroxides. The need of anti-oxidant can be prevented by the usage of saturated fatty acids during the preparation of the lipid core [220]. In the formation of emulsomes, like in the case of liposomes, cholesterol is essential component for the system that influences the stability of

emulsomal systems and plays an important role in the drug encapsulation [221-224].

amphiphilic nature and disassociate from the lipid bilayer or micelle [179].

28 Application of Nanotechnology in Drug Delivery

ments in the aqueous compartments of surrounding phospholipid layers.

drug delivery.

The development of emulsomes, however, is still largely empirical, and in vitro models that are predictive of oral bioavailability enhancement are lacking. There is a need for in vitro methods for predicting the dynamic changes involving the drug in the gut in order to monitor the solubilization state of the drug in vivo. Attention also needs to be paid to the interactions between lipid systems and the pharmacologically active substance. The characteristics of various lipid formulations also need to be understood, so that guidelines can be established that allow identification of suitable candidate formulations at an early stage. Future research should involve human bioavailability studies as well as more basic studies on the mechanisms of action of this fascinating and diverse group of formulations.

Unilamellar vesicles or liposomes are commonly used as simple cell models and as drug delivery vehicles to follow the release kinetics of lipophilic drugs that require compartmental models in its therapeutics and triggers. The localization of the drug at the site of action, rate of achieving the therapeutic index and circulation lifetime are the key parameters for a liposome. Lately, their arises a need for a multi-compartment structure consisting of drugloaded liposomes encapsulated within another bilayer, is a promising drug carrier with better retention and stability due to prevention enzymes or proteins reaching the interior bilayers. A vesosome is a more or less heterogeneous, aggregated, large lipid bilayer enclosing multiple, smaller liposomes that offer a second barrier of protection for interior compartments and can also serve as the anchor for active targeting components [226, 76]. The multi-compartment structure of vesosome can also allow for independent optimization of the interior compart‐ ments and exterior bilayer; however, just the bilayer-within-a-bilayer structure of the veso‐ some is sufficient to increase drug retention from minutes to hours [227, 228].

In nature, eukaryotes increased their ability to optimize their response to their surroundings by developing multiple compartments, each of which has a distinct bilayer membrane, usually of quite varied composition and physical structure. Mimicking this natural progression to nested bilayer compartments led to the development of the vesosome, or vesicles deliberately trapped within another vesicle. The vesosome has distinct inner compartments separated from the external membrane; each compartment can encapsulate different materials and have different bilayer compositions. In addition, while it has proven difficult to encapsulate anything larger than molecular solutions within lipid bilayers by conventional vesicle selfassembly, the vesosome construction process lends itself to trapping colloidal particles and biological macromolecules relatively efficiently [229, 230]. The nested bilayer compartments of the vesosome provide a degree of freedom for optimization not possible with a single membrane enclosed compartment and a more realistic approximation of higher order biolog‐ ical organization.

The vesosome structure could be used to deliver a cocktail of antibiotics or antimicrobials to sites at a fixed ratio; such mixtures have been shown to act synergistically when delivered in a single liposome [231]. Such multi-drug formulations may be useful to avoid inducing pathogen resistance to a single drug.

expression of highly immunogenenic genes for immune self-attack and sensitization of cells

Recently, the studies on gene delivery into eukaryotic cells by the use of non-viral-lipid-based macromolecular delivery systems have been experiencing a growing interest owing to the appearance of clinical protocols for gene therapy. Although the efficiency and specificity of such non-viral delivery systems are not yet very high, some of the problems concerning transfection methods are being successfully solved. To date, the transfection mediators that ensure effective and directed gene delivery into various cells have been created. Transfection of plasmid DNA is closely connected to the problem of condensation of its molecule since the plasmid is too large (13-15 kb) to effectively overcome the cellular membrane barrier. Besides, free DNA has to be protected from destruction by endogenous nucleases. Lastly, it is necessary

Genosomes are the artificial functional complexes for functional gene or DNA delivery to cell [238]. For the production of genosomes, cationic phospholipids were found to be more suitable because they possess high biodegradability and stability in the blood stream. Gene delivery is a vast area of research and a detailed summary of work in that field is beyond the scope of this

Archaesomes One or more lipids containing diether linkages High stability at several conditions Niosomes Non-ionic surfactant and cholesterol Less prone to action of bile salts

Transfersomes Lipid supramolecular aggregates More flexible hence better transdermal

Vesesomes Multilamellar liposomes Multidrug formulations are possible

High loading of drugs

Liposomes as Potential Drug Carrier Systems for Drug Delivery

http://dx.doi.org/10.5772/58459

31

More distruptive in the skin lipid bilayer organization hence better transdermal

Intracellular delivery of antigens, drugs

Better for encapsulation of hydrophobic

Suitable for gene delivery

delivery

delivery

and DNA

drugs

New generation liposomes and their features are summarized in Table 2.

**Type Main constituent Advantage**

and free fatty acids. Two to seven bilayer shells

Cryptosomes Phospholipids and polaxamers or PEG More stable

Novasomes Monoester of polyoxyethylene fatty acids, cholesterol

Virosomes Lipids surface modified with fusogenic viral envelope

Emulsomes Internal solid fat core surrounded by phospholipid

Genosomes Complex of cationic phospholipids and a functional

Ethosomes Phospholipids and alcohol in relatively high concentration

proteins

bilayer

gene or DNA

**Table 2.** New generation liposomes and their features.

to other treatments.

chapter.

Liposomes Phospholipids

to neutralize the negative charge on DNA.

As vesosomes are simply liposomes within liposomes, it should be possible to directly translate the extensive body of research on liposome drug delivery to the vesosome with only minor changes, and perhaps significant major improvements. The vesosome is created by simply selfassembly steps very similar to those used in making conventional unilamellar liposomes [229]. An important question is whether such additional effort in developing new structures will provide a therapeutic benefit over direct injection of the free drug or drug delivery by conventional unilamellar liposomes. The most obvious potential application for the vesosome is for drugs that have already shown increased efficacy by delivery with conventional liposomes. As an example, ciprofloxacin (cipro), a synthetic bactericidal fluoroquinolone antibiotic with broad spectrum efficacy, is released much more quickly from unilamellar liposomes in serum relative to saline [232, 233]. Conventional pH-loaded liposomes can retain essentially all encapsulated ciprofloxacin when stored in buffer for 12 weeks at 21 0C and 8 weeks at 37 0C [234, 235]. Although liposomal cipro has shown increased efficacy due to prolonged residence of cipro in the blood (free cipro is cleared in minutes), the half-life of release from the liposomes was only 1 hour, yet the liposomes themselves circulated for more than 24 hours [232, 235]. A second example is vincristine, a naturally occurring dimeric catharanthus alkaloid that has been used extensively as an antitumor agent since 1960's. The therapeutic activity of vincristine is dictated by the duration of therapeutic concentrations at the tumor site [236, 238, 239]. However, conventional liposomes, while offering improved bioavailability, also cannot encapsulate vincristine for sufficient time to give optimal results [234, 236, 237]. Future work will determine if multiple compartment structures like vesosome give sufficient enhancement of small drug entrapment to lead to new therapeutics.

Genetics play an increasingly important role in medicine and is used routinely to diagnose diseases and to understand malfunctions at the molecular level. The active approach of trying to amend genetic defects or insufficiencies is a logical next step. Major elements in the successful advance of gene therapy are identification of the disease and target cells, tissues and organs as well as construction of appropriate gene vectors, effective gene transfer and expression in the targeted cells. Many inherited diseases follow the Mendelian inheritance pattern in which the cause is due to a single genetic defect. Because the existing therapeutic treatments of such diseases are in most cases very limited, it is hoped that by transfecting appropriate cells with the correct gene or by adding a missing one, the disease could be alleviated. Examples of such potential treatments are for cystic fibrosis, hemophilia, sickle cell anemia or hypercholesterimia and mutant tumor suppressor genes.

The aim of gene therapy is to deliver DNA, RNA or antisense sequences to appropriate cells in order to alleviate symptoms or prevent the occurrence of a particular disease, i.e. repair the defect and also its cause. The major approaches to gene therapy include gene replacement, addition of genes for production of natural toxins, stimulation of the immune system or over expression of highly immunogenenic genes for immune self-attack and sensitization of cells to other treatments.

The vesosome structure could be used to deliver a cocktail of antibiotics or antimicrobials to sites at a fixed ratio; such mixtures have been shown to act synergistically when delivered in a single liposome [231]. Such multi-drug formulations may be useful to avoid inducing

As vesosomes are simply liposomes within liposomes, it should be possible to directly translate the extensive body of research on liposome drug delivery to the vesosome with only minor changes, and perhaps significant major improvements. The vesosome is created by simply selfassembly steps very similar to those used in making conventional unilamellar liposomes [229]. An important question is whether such additional effort in developing new structures will provide a therapeutic benefit over direct injection of the free drug or drug delivery by conventional unilamellar liposomes. The most obvious potential application for the vesosome is for drugs that have already shown increased efficacy by delivery with conventional liposomes. As an example, ciprofloxacin (cipro), a synthetic bactericidal fluoroquinolone antibiotic with broad spectrum efficacy, is released much more quickly from unilamellar liposomes in serum relative to saline [232, 233]. Conventional pH-loaded liposomes can retain essentially all encapsulated ciprofloxacin when stored in buffer for 12 weeks at 21 0C and 8 weeks at 37 0C [234, 235]. Although liposomal cipro has shown increased efficacy due to prolonged residence of cipro in the blood (free cipro is cleared in minutes), the half-life of release from the liposomes was only 1 hour, yet the liposomes themselves circulated for more than 24 hours [232, 235]. A second example is vincristine, a naturally occurring dimeric catharanthus alkaloid that has been used extensively as an antitumor agent since 1960's. The therapeutic activity of vincristine is dictated by the duration of therapeutic concentrations at the tumor site [236, 238, 239]. However, conventional liposomes, while offering improved bioavailability, also cannot encapsulate vincristine for sufficient time to give optimal results [234, 236, 237]. Future work will determine if multiple compartment structures like vesosome

give sufficient enhancement of small drug entrapment to lead to new therapeutics.

anemia or hypercholesterimia and mutant tumor suppressor genes.

Genetics play an increasingly important role in medicine and is used routinely to diagnose diseases and to understand malfunctions at the molecular level. The active approach of trying to amend genetic defects or insufficiencies is a logical next step. Major elements in the successful advance of gene therapy are identification of the disease and target cells, tissues and organs as well as construction of appropriate gene vectors, effective gene transfer and expression in the targeted cells. Many inherited diseases follow the Mendelian inheritance pattern in which the cause is due to a single genetic defect. Because the existing therapeutic treatments of such diseases are in most cases very limited, it is hoped that by transfecting appropriate cells with the correct gene or by adding a missing one, the disease could be alleviated. Examples of such potential treatments are for cystic fibrosis, hemophilia, sickle cell

The aim of gene therapy is to deliver DNA, RNA or antisense sequences to appropriate cells in order to alleviate symptoms or prevent the occurrence of a particular disease, i.e. repair the defect and also its cause. The major approaches to gene therapy include gene replacement, addition of genes for production of natural toxins, stimulation of the immune system or over

pathogen resistance to a single drug.

30 Application of Nanotechnology in Drug Delivery

Recently, the studies on gene delivery into eukaryotic cells by the use of non-viral-lipid-based macromolecular delivery systems have been experiencing a growing interest owing to the appearance of clinical protocols for gene therapy. Although the efficiency and specificity of such non-viral delivery systems are not yet very high, some of the problems concerning transfection methods are being successfully solved. To date, the transfection mediators that ensure effective and directed gene delivery into various cells have been created. Transfection of plasmid DNA is closely connected to the problem of condensation of its molecule since the plasmid is too large (13-15 kb) to effectively overcome the cellular membrane barrier. Besides, free DNA has to be protected from destruction by endogenous nucleases. Lastly, it is necessary to neutralize the negative charge on DNA.

Genosomes are the artificial functional complexes for functional gene or DNA delivery to cell [238]. For the production of genosomes, cationic phospholipids were found to be more suitable because they possess high biodegradability and stability in the blood stream. Gene delivery is a vast area of research and a detailed summary of work in that field is beyond the scope of this chapter.


New generation liposomes and their features are summarized in Table 2.

**Table 2.** New generation liposomes and their features.

Extensively motivated by the need to increase the stability and bioavailability of drugs, and to reduce their side effects by targeting to the site of action, research in new drug delivery vehicles has taken giant steps. Liposomes and their derivatives, so called new generation liposomes, present a vast area in this field where several advances have already been achieved as summarized in this chapter. However, still further research is required to overcome the limitations faced today in terms of prolonged stability, drug loading and active targeting.

[2] Bangham A.D, Standish M.M, Watkins J.C. Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids. Journal of Molecular Biology 1965;13 238-252. [3] Gregoriadis G, Florene A.T. Liposomes in Drug Delivery: Clinical, Diagnostic and

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[4] Van Rooijen N, van Nieuwmegen R. Liposomes in Immunology: Multilammellar Phosphatidylcholine Liposome as a Simple Biodegradable and Harmless Adjuvant without any Immunogenic Activity of its Own. Immunology Community 1980;9

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[10] Gregoriadis G, Ryman B.E. Liposomes as Carriers of Enzymes or Drugs: A New Ap‐ proach to the Treatment of Storage Diseases. Biochemcal Journal 1971;124 58P.

[12] Gregoradis G. The Carrier Potential of Liposomes in Biology and Medicine. Part

[13] Gregoradis G. The Carrier Potential of Liposomes in Biology and Medicine. Part 2,

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243-356.

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tobios 1983;37 (1983) 21-26.

#### **8. Conclusion**

In the last decade from the concept of clinical utility of liposomes to their recognized position in mainstream of drug delivery systems, the path has been long and winding. The liposome systems have been explored in the clinic for applications as diverse as sites of infection and imaging, for vaccine, gene delivery and small molecular drugs, for treatment of infections and for cancer treatment, for lung disease and for skin conditions etc. Several liposomal formula‐ tions are already on the market, while quite a few are still in the pipeline for treatment of diseases. Conventional techniques for liposome preparation and size reduction remain popular as these are simple to implement and do not require sophisticated equipment. However, not all laboratory scale techniques are easy to scale-up for industrial liposome production. Many conventional methods, for preparing small and large unilamellar vesicles, involve use of either water miscible/immiscible organic solvents or detergent molecules. The need for improvements in the design and stability of liposomal diagnostic and therapeutic systems will continue to motivate innovative and efficient routes to their production.

### **Author details**

Melis Çağdaş<sup>1</sup> , Ali Demir Sezer2 and Seyda Bucak3\*

\*Address all correspondence to: seyda@yeditepe.edu.tr

1 Department of Chemistry, Boğaziçi University, Bebek, Istanbul, Turkey

2 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, Haydarpaşa, Istanbul, Turkey

3 Department of Chemical Engineering, Yeditepe University, Kayışdağı, Istanbul, Turkey

#### **References**

[1] Bangham A.D., editor. The Liposome Letters. Academic Press; 1983.

[2] Bangham A.D, Standish M.M, Watkins J.C. Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids. Journal of Molecular Biology 1965;13 238-252.

Extensively motivated by the need to increase the stability and bioavailability of drugs, and to reduce their side effects by targeting to the site of action, research in new drug delivery vehicles has taken giant steps. Liposomes and their derivatives, so called new generation liposomes, present a vast area in this field where several advances have already been achieved as summarized in this chapter. However, still further research is required to overcome the limitations faced today in terms of prolonged stability, drug loading and active targeting.

In the last decade from the concept of clinical utility of liposomes to their recognized position in mainstream of drug delivery systems, the path has been long and winding. The liposome systems have been explored in the clinic for applications as diverse as sites of infection and imaging, for vaccine, gene delivery and small molecular drugs, for treatment of infections and for cancer treatment, for lung disease and for skin conditions etc. Several liposomal formula‐ tions are already on the market, while quite a few are still in the pipeline for treatment of diseases. Conventional techniques for liposome preparation and size reduction remain popular as these are simple to implement and do not require sophisticated equipment. However, not all laboratory scale techniques are easy to scale-up for industrial liposome production. Many conventional methods, for preparing small and large unilamellar vesicles, involve use of either water miscible/immiscible organic solvents or detergent molecules. The need for improvements in the design and stability of liposomal diagnostic and therapeutic

systems will continue to motivate innovative and efficient routes to their production.

and Seyda Bucak3\*

2 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University,

3 Department of Chemical Engineering, Yeditepe University, Kayışdağı, Istanbul, Turkey

1 Department of Chemistry, Boğaziçi University, Bebek, Istanbul, Turkey

[1] Bangham A.D., editor. The Liposome Letters. Academic Press; 1983.

**8. Conclusion**

32 Application of Nanotechnology in Drug Delivery

**Author details**

Haydarpaşa, Istanbul, Turkey

, Ali Demir Sezer2

\*Address all correspondence to: seyda@yeditepe.edu.tr

Melis Çağdaş<sup>1</sup>

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**Chapter 2**

**Techniques for the Preparation of Solid Lipid Nano and**

SLN are nanoparticles made of solid lipids with a photon correlation spectroscopy (PCS) mean

General ingredients include solid lipid(s), surfactant(s) and water. The term lipid is used here in a broad sense and includes triglycerides (e.g. tristearin), partial glycerides, fatty acids (e.g. stearic acid), steroids (e.g. cholesterol) and waxes (e.g. cetyl palmitate). All classes of surfac‐ tants (with respect to charge and molecular weight) have been used to stabilize the lipid

SLN were developed in the early 1990s and up today they have been considered to be promising drug carrier systems, especially with the aim to give a sustained release profile to the incorporated active substances. In fact, compared to liquid lipid formulations, such as nanoemulsions, drug mobility is really lower in solid lipids than in liquid oils. Compared to polymeric nanoparticles, they show a better biocompatibility since they're made of lipids similar to physiological one, so the toxicity is reduced. Moreover SLN are physico-chemically stable and can be produced easily on a large industrial scale, and raw material and production

SLM have equivalent composition to SLN, but higher particle size (>1000 nm), meaning that

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

their application domains and administration routes can be different [3].

**Microparticles**

Luigi Battaglia, Marina Gallarate,

Elena Peira and Daniela Chirio

http://dx.doi.org/10.5772/58405

**1. Introduction**

dispersion [2].

costs are relatively low [1].

Pier Paolo Panciani, Elena Ugazio, Simona Sapino,

Additional information is available at the end of the chapter

diameter approximately between 50 and 1000 nm [1].


**Chapter 2**
