Advantages of vesicular drug delivery system

· Prolong the existence of the drug in systemic circulation, and perhaps, reduces the toxicity if selective uptake can be achieved due to the delivery of drug directly to the site of infection.

· Improves the bioavailability especially in the case of poorly soluble drugs.

· Both hydrophilic and lipophilic drugs can be incorporated.

· Delays elimination of rapidly metabolizable drugs and thus function as sustained release systems.

Along with the number of advantages vesicular system has some serious disadvantages which restrict their use: The conventional vesicular system have some problems such as particular ( liposomes nanoparticles, microemulsion) and externally triggered (e.g. temperature, pH, or magnetic sensitive) carriers load drugs passively, which may lead to low drug loading efficiency and drug leakage in preparation, preservation and transport in vivo. Some vesicular system associated problems are mentioned in table 1.

A potential solution for these problems is the use of self assembled nanoparticles (SAN) i.e., the pharmacosomes. The outstanding characteristic of SAN over common nanoparticles or liposomes is that they are nearly wholly composed of amphiphilic prodrugs, so that high drug-loaded amount and very low drug leakage are archived easily. In addition, the amphiphilic monomers of SAN would like to permeate biomembranes of targets provided that SAN were decomposed on target surfaces. Pharmacosomes can be considered as one of SAN based on the various theories. Pharmacosomes are like a panacea for most of the problems associated with liposomes, transferosomes, niosomes, and so forth. They are an efficient tool to achieve desired therapeutic goals such as drug targeting and controlled release.

The vesicular systems are highly ordered assemblies of one or several concentric lipid bilayers formed, when certain amphiphillic building blocks are confronted with water. Vesicles can be formed from a diverse range of amphiphillic building blocks. The main aim is to control degradation of drug and loss prevention of harmful side effects and increase the availability of the drug at the disease site. Encapsulation of a drug in vesicular structures can be predicted to prolong the existence of the drug in systemic circulation and perhaps, reduces the toxicity if selective uptake can be achieved. Lipid vesicles are one type of many experimental models of biomembranes which evolved successfully, as vehicles for controlled delivery. For the treatment of intracellular infections, conventional chemotherapy is not effective due to limited permeation of drugs into cells. This can overcome by the use of vesicular drug delivery systems.

Types of vesicular systems

lternative terminology has been used to describe vesicular systems but all researchers agree that they are of a similar morphology but with different functions and/or compositions.

Liposomes are vesicles in which one or more lipid bilayer(s) entrap an aqueous volume. Their major components are usually phospholipids with or without cholesterol. The stratum corneum lipid liposomes (SCLL) are vesicular systems made of lipids with a composition similar to the lipids found in the outer layer of human skin, the stratum corneum. Transfersomes (ultra deformable vesicles) are structurally similar to liposomes but they differ in function. Phospholipids are the major components but an additional surfactant acts as an edge activator to modify elasticity and increase deformability. Ethosomes are phospholipids vesicles, which include ethanol to increase elasticity, whereas niosomes comprise surfactants together with cholesterol and may include small proportions of phospholipids.

Mechanisms of action of vesicles as skin drug delivery systems

Various mechanisms have been reported for improved transdermal drug delivery from vesicular systems.

Free Drug Mechanism

According to this process, the drug has to be released from the vesicles before independent permeation into and through the skin. In this case, vesicles can be considered only as carriers that can control drug release with drug permeation depending on its physicochemical characteristics. To investigate this possibility, the transepidermal flux profile obtained from different liposome formulations was compared with the corresponding in vitro drug release profile. For all preparations, the peak flux of estradiol through skin appeared at a time during which drug release was negligible. This suggests that a free drug mechanism did not operate for the tested standard and deformable liposome formulations.

Penetration Enhancing Mechanism

According to this mechanism, vesicle components may enter the skin as monomers disrupting the packing characteristics of the SC lipid bilayers and thus enhancing drug permeation. The penetration enhancing effect of egg lecithin (included in a drug solution in propylene glycol) was first recorded two decades ago, after in vitro and in vivo animal studies. It was concluded that lecithin enhances the transdermal delivery of bunazosin hydrochloride by lowering the permeability barrier of the skin. This early finding suggested the possible accelerant effect of a liposome component.

Freeze fracture electron microscopy and small angle X-ray scattering studies, performed 48 hours after incubating human SC in liposome dispersions revealed that vesicle components can change the ultrastructure of the intercellular lipid regions, indicative of penetration enhancing effects. It was concluded that vesicles made of lipids with relatively small hydrophilic head groups can produce marked interaction with human stratum corneum lipids in vitro. After application of soybean PC liposomes to human epidermis reconstituted in vitro, electron microscopy showed the presence of dose-dependent alterations in the morphology of both the SC and the viable epidermis with shrunken lipid droplets formed between the corneocytes. This supported further the previous findings of an enhancing action from liposomes.

In another study, differential scanning calorimetric investigations performed to human SC treated (non-occlusively) with dimyristoylphosphatidylcholine (DMPC) liposomes showed changes in the enthalpy of the lipid-related transitions of the SC. In addition, depending on composition, vesicles may produce an enhancing effect (shown by skin pre-treatment), may penetrate deep into the stratum corneum or may fuse and mix with skin lipid. Liposomes containing Di-Oleyl-Phosphatidyl-Ethanolamine (DOPE) or lyso-PC produced the greatest effect. Vesicles containing DOPE can fuse and mix with skin lipids and loosen their structure. This was evidenced by the interactions of these vesicles with stratum corneum lipid liposomes; it was suggested that the conical shape of DOPE was essential for this effect. Both the PE and dioleyl moieties were essential, as nano-structures containing PE (with other fatty acid chains) provided lower enhancing effects compared with the DOPE liposomes. More recently, the same group recorded deeper penetration of a lipophilic fluorescent probe into SC after application of PC liposomes containing 32% ethanol compared with ethanol-free vesicles. Ethanol did not affect the penetration pattern from DOPE-containing liposomes, but addition of ethanol increased the mixing of both vesicles with SCLL. In addition, ethanol-containing nano-structures (both types) destabilized skin lipid-based liposomes as evidenced by increased calcein release from SCLL preparations compared with control (containing the same concentration of ethanol). These studies provide further evidence for the penetration enhancing effect of liposome components. The effect of skin pretreatment with PC liposomes on the transdermal delivery of a variety of corticosteroids from creams was evaluated by the human skin blanching assay. The pre-treatment increased the blanching response and reduced the tachyphylaxis for all preparations except clobetasone butyrate. The authors explained this effect on the basis that PC may form a thin film on the skin surface into which corticosteroids can preferentially partition, or that PC can partition into SC and thus enhance delivery by influencing the partitioning of corticosteroid into skin.

Vesicle adsorption to and or fusion with the stratum corneum

The processes of adhesion onto the skin surface and fusion or mixing with the lipid matrix of stratum corneum have been suggested for liposome lipids. The phospholipid components of liposomes can rapidly enter the skin with the drugs following their fate. Phospholipids increased the partitioning of estradiol, progesterone and propranolol into the stratum corneum lipid bilayers. It was also reported that the phospholipid component of liposomes can increase the continuity of the lipid matrix of the skin thus facilitating the movement of lipophilic molecules. Based on this suggestion, we should expect improved drug uptake from a saturated aqueous solution after skin pre-treatment with empty vesicles. Consequently, an uptake study was conducted in which stratum corneum membranes were dipped for a short time (10 minutes) into medicated vesicles or into an aqueous drug solution with or without pre-treatment with empty vesicles. Drug uptake was increased only from medicated carriers and the uptake ratios (UR) between the vesicles and solution ranged from 23 to 29 with no significant differences between ultradeformable and standard liposomes. Correlating the superiority of ultradeformable vesicles over standard liposomes in increasing transepidermal flux, with no significant difference found in the UR at short contact time, suggests that deformable vesicles either improved drug diffusion or penetrated deeper in the epidermis, thus allowing more efficient drug clearance.

Intact vesicular skin penetration mechanism

Liposomal formulations were superior in the treatment of eczema but not for psoriasis compared to a traditional gel. This finding suggested that vesicles can penetrate diseased skin with its ruptured SC (as in eczema) but cannot invade skin with hyperkeratosis, as in psoriasis. Subsequently, fluoromicrographic studies showed that intact small unilamellar vesicles (SUVs) containing PC and CH penetrated no deeper than the stratum corneum.

The ratio of radiolabelled components of liposomal preparations was constant throughout the skin strata after topical application of liposomes with dual labelled components; the findings were explained as possible molecular mixing of liposomal bilayers with the SC bilayers. The ratio of the radiolabelled marker to liposome components was also constant throughout skin strata. The explanation given by the authors (molecular mixing) may not justify equal ratios of the dual label in the deeper skin strata. These findings may suggest possible carrier skin penetration. Similar findings were reported again for both phospholipid and stratum corneum lipid-based liposomes.

Liposomes⁵

Liposomes consist of one or more concentric lipid bilayers, which enclose an internal aqueous volume(s). For drug delivery applications liposomes are usually unilamellar and range in diameter from about 50 – 150 nm. Larger liposomes are rapidly removed from the blood circulation. Liposomes are unique in their ability to accommodate drugs, which differ widely in physicochemical properties such as polarity, charge and size. Sites in liposomes where these drugs can localize include the liposome bilayer with its hydrophobic hydrocarbon chain core, its large polar surface, which can be neutral or charged and the internal aqueous space. The word drug is used as a generic term and refers to conventional drugs.

Liposomes are just hollow spheres of lipids, i.e. some lipids form membranes that close on themselves forming liposomes. The main component of liposome membranes is dipalmitoyl phosphatidil choline. However, some other compounds are added in order to improve stability or other structural properties. Two compounds added are: dipalmitoyl phosphatidil glycerol (DPPG or PG) and cholesterol. Apparently, cholesterol has the effect of making the membrane less permeable by filling up holes or disruptions. When phospholipids are dispersed in water, they spontaneously form closed structure with internal aqueous environment bounded by phospholipid bilayer membranes, thus forms vesicular system called as liposomes. About 40 years ago, Bangham and co-workers defined liposomes as the small vesicle of spherical shape that can be produced from cholesterols, non toxic surfactants, Sphingolipids, glycolipids, long chain fatty acids and even membrane protein. , which has become the versatile tool in biology, biochemistry and medicine today. In 1960s, liposome has been used as a carrier to deliver a wide variety of compounds in its aqueous compartment. They can encapsulate and effectively deliver both hydrophilic and lipophilic substances and may be used as a non-toxic vehicle for insoluble drugs. Liposome can be formulated and processed to differ in size, composition, charge and lamellarity. The most important use of liposomes is expected to be in biotechnology, medicine and pharmacology, where they serves as vehicles for controlling delivery of entrapped medicament viz. immunomodulator, cancer chemotherapeutics, diagnostics, antibiotics, antifungal, ophthalmic, antiasthmatic, vaccines, enzyme and genetic material. Till the date liposomal formulations of antitumor drugs and antifungal agents have been commercialized on large scale. In coming years, one sees an enormous potential in liposome manufacturing as more and more industrial manufacturing methods are developed. Though there are many hurdles in their formulation and developments, which are not negligible. The source of the lipids and stability of the phospholipids, which are considered critical excipients, plays a key role in the characterization of product performance Moreover; its clinical use has found limited application due to the remarkable barrier properties of the stratum corneum, the outermost layer of skin.

Advantages

· Phospholipids are one of the few solubilizers that are well tolerated.

· Liposomes may increase the solubility of insoluble drugs between one hundred to ten thousand fold.

· In the small intestine, liposomes are digested in the presence of bile and enzymes. The solubilized compound is liberated and further solubilized in bile and digested lipids.

· Ideal models for biological membranes as well as efficient carriers for drugs, diagnostics, vaccines, nutrients and other bioactive agents.

· Both water soluble and water insoluble compounds can be delivered.

Niosomes¹⁸

Niosomes are formations of vesicles by hydrating mixture of cholesterol and non-ionic surfactants. These are formed by self assembly of non-ionic surfactants in aqueous media as spherical, unilamellar, multilamellar system and polyhedral structures in addition to inverse structures which appear only in nonaqueous solvent. Niosomes are non-ionic surfactant vesicles obtained on hydration of synthetic nonionic surfactants, with or without incorporation of cholesterol or other lipids. They are vesicular systems similar to liposomes that can be used as carriers of amphiphilic and lipophilic drugs. The vesicles are defined to be composed of or relating to small, saclike bodies. In niosomes, the vesicles forming amphiphile is a non-ionic surfactant which is usually stabilized by addition of cholesterol and small amount of anionic surfactant such as dicetyl phosphate. Niosomes and liposomes are equiactive in drug delivery potential and both increase drug efficacy as compared with that of free drug. Niosomes are preferred over liposomes because the former exhibit high chemical stability and economy. One of the reasons for preparing niosomes is the assumed higher chemical stability of the surfactants than that of phospholipids, which are used in the preparation of liposomes. Due to the presence of ester bond, phospholipids are easily hydrolysed.

Advantages

· They improve the therapeutic performance of the drug molecules by delayed clearance from the circulation, protecting the drug from biological environment and restricting effects to target cells.

· Handling and storage of surfactants requires no special conditions.

· They improve oral bioavailability of poorly absorbed drugs and enhance skin penetration of drugs.

· They can be made to reach the site of action by oral, parenteral as well as topical routes.

· They possess an infrastructure consisting of hydrophilic, amphiphilic and lipophilic moieties together and as a result can accommodate drug molecules with a wide range of solubilities.

Pharmacosomes⁷

These are defined as colloidal dispersions of drugs covalently bound to lipids and may exist as ultrafine vesicular, micellar or hexagonal aggregates, depending on the chemical structure of drug-lipid complex. The prodrug conjoins hydrophilic and lipophilic properties and therefore acquires amphiphilic characters and was found to reduce interfacial tension and thus at higher concentrations exhibits mesomorphic behaviour. Because the system is formed by linking a drug (pharmakon) to a carrier (soma), they are called pharmacosomes. Pharmacosomes are bearing unique advantages over liposome and noisome vesicles and have come up as potential alternative to conventional vesicles.

They are the colloidal dispersions of drugs covalently bound to lipids. Depending upon the chemical structure of the drug–lipid complex they may exist as ultrafine vesicular, micellar, or hexagonal aggregates. As the system is formed by linking a drug (pharmakon) to a carrier (soma), they are termed as “pharmacosomes”. They are an effective tool to achieve desired therapeutic goals such as drug targeting and controlled release. Any drug possessing an active hydrogen atom (-COOH, -OH, -NH2, etc.) can be esterified to the lipid, with or without spacer chain that strongly result in an amphiphilic compound, which will facilitate membrane, tissue, or cell wall transfer, in the organism. The criterion for the development of the vesicular pharmacosome is dependent on surface and bulk interactions of lipids with drug. These amphipathic prodrug mesogens may serve as building blocks by participating in supramolecular assemblages and thus acquire a colloidal state. The prodrug conjoins hydrophilic and lipophilic properties (thereby acquiring amphiphilic characteristics), reduce interfacial tension, and, at higher concentrations, exhibit mesomorphic behavior. Because of a decrease in interfacial tension, the contact area increases, therefore increasing bioavailability.

Advantages

· They are an effective tool to achieve desired therapeutic goals such as drug targeting and controlled release.

· High and predetermined entrapment efficiency as drug and carrier form a stoichiometrically defined unit covalently linked together.

· Volume of inclusion doesn’t influence entrapment efficiency.

· No need of removing the free, unentrapped drug from the formulation which is required in the case of liposomes.

· Improves bioavailability especially in the case of poorly soluble drugs.

· Drug carriers such as liposomes, nanoparticles, micro emulsions which have lead to low drug-loading efficiency, physical stability such as fusion, aggregation, sedimentation and drug leakage during preparation, preservation etc is absent in pharmacosomes

· Suitable for both hydrophilic and lipophilic drugs. The aqueous solution of these amphiphiles exhibits concentration dependant aggregation.

· High and predetermined entrapment efficiency as drug and carrier are covalently linked together.

· As drug is covalently bound membrane fluidity has no effect on release rate, but in turn depends upon the phase transition temperature of the drug lipid complex. No leakage of drug take place as the drug is covalently linked to the carrier

· Drug release from pharmacosomes is by hydrolysis.

· Reduction in adverse effects and toxicity.

· Reduced cost of therapy.

· Their degradation velocity into active drug molecule, after absorption depends very much on the size and functional groups of the drug molecule, the chain length of lipids and the spacer.

Advantages of Pharmacosomes over Liposomes

· In case of pharmacosomes, volume of inclusion does not influence entrapment efficiency. On the other hand, in case of liposomes, the volume of inclusion has great influence on entrapment efficiency.

· In pharmacosomes membrane fluidity depends upon the phase transition temperature of the drug lipid complex but it has no effect on release date because the drug is covalently bound. In liposomes, the lipid composition decides its membrane fluidity, which affects the rate of drug release and physical stability of the system.

· Drug release from pharmacosomes is by hydrolysis (including enzymatic) unlike liposomes the release of drug is by diffusion through bilayer, desorption from the surface or degradation of liposomes.

· Unlike liposomes in pharmacosomes there is no need of following the tedious, time consuming step for removing the free, un-entrapped drug from the formulation.

· In liposomes there are chances of sedimentation and leaching of drug but in pharmacosomes the leakage of drug does not take place because the drug is covalently linked to the carrier.

Ethosomes⁶

Ethosomes are lipid-based elastic vesicular systems embodying ethanol in relatively high concentrations which enhance the topical drug delivery. The presence of ethanol prolongs the physical stability of the ethosomes with respect to liposomes. The enhanced delivery of actives incorporated in the ethosomes can be ascribed to the interactions between ethosomes and skin lipids. That may open the new pathways due to the malleability and fusion of ethosomes with skin lipids, which results in the penetration of drug into deeper skin layers. Interaction between skin and ethosomes: The enhanced delivery of actives using ethosomes over liposomes can be ascribed to an interaction between ethosomes and skin lipids. A possible mechanism for this interaction has been proposed. It is thought that the first part of the mechanism is due to the ‘ethanol effect’, whereby intercalation of the ethanol into intercellular lipids increasing lipid fluidity and decreases the density of the lipid multilayer. This is followed by the ‘ethosomes effect’, which includes inter lipid penetration and permeation by the opening of new pathways due to the malleability and fusion of ethosomes with skin lipids, resulting in the release of the drug in deep layers of the skin.

Permeation enhancers increase the permeability of the skin, so that the drugs can cross through the skin easily. Unlike classic liposomes, that are known mainly to deliver drugs to the outer layers of skin, ethosomes can enhance permeation through the stratum corneum barrier. Ethosomes permeate through the skin layers more rapidly and possess significantly higher transdermal flux in comparison to conventional liposomes. Ethosomes are lipid vesicles containing phospholipids, alcohol (ethanol and isopropyl alcohol) in relatively high concentration and water. Ethosomes are soft vesicles made of phospholipids and ethanol (in higher quantity) and water. Ethosomes can entrap drug molecule with various physicochemical characteristics i.e. of hydrophilic, lipophilic, or amphiphillic. The size range of ethosomes may vary from tens of nanometers to microns (µ).

The vesicles have been well known for their importance in cellular communication and particle transportation for many years. Researchers have understood the properties of vesicles structure for use in better drug delivery within their cavities, which would to tag the vesicle for cell specificity. One of the major advances in vesicle research was finding a vesicle derivative, known as an ethosomes. Ethosomes are non-invasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. These are soft, malleable vesicles tailored for enhanced delivery of active agents. They are composed mainly of phospholipids, (phosphatidylcholine, phosphatidylserine, phosphatitidic acid), high concentration of ethanol and water. The high concentration of ethanol makes the ethosomes unique, as ethanol is known for its disturbance of skin lipid bilayer organization therefore, when integrated into a vesicle membrane it gives that vesicle the ability to penetrate the stratum corneum. Also because of their high ethanol concentration, the lipid membrane is packed less tightly than conventional vesicles but has equivalent stability, allowing a more malleable structure and improved drug distribution ability in stratum corneum lipids.

Advantages of ethosomal drug delivery

· Delivery of large molecules (peptides, protein molecules) is possible.

· It contains non-toxic raw material in formulation.

· Enhanced permeation of drug through skin for transdermal drug delivery.

· Ethosomal drug delivery system can be applied widely in pharmaceutical, veterinary, cosmetic fields.

· High patient compliance: The ethosomal drug is administrated in semisolid form (gel or cream) hence producing high patient compliance.

· Simple method for drug delivery in comparison to iontophoresis and phonophoresis and other complicated methods

· The Ethosomal system is passive, non-invasive and is available for immediate commercialization.

Table no 4. Applications of ethosomes

Drug	Purpose of ethosome	Applications
Zidovudine	Better cellular uptake	Anti-HIV
Fluconazole	Poor skin permeation	In candidiasis
Diclofenac	Selective targeting the cells	NSAIDs
Methotrexate	Poor skin permeation	In psoriasis
Insulin	GIT degradation	In diabetes

Transferosomes¹⁰

Liposomal as well as niosomal systems, are not suitable for transdermal delivery, because of their poor skin permeability, breaking of vesicles, leakage of drug, aggregation and fusion of vesicles. To overcome these problems, a new type of carrier system called ‘Transferosomes’ has recently been introduced, which is capable of transdermal delivery of low as well as high molecular weight drugs.

Transferosomes are specially optimized, ultra deformable (ultraflexible) lipid supramolecular aggregates, which are able to penetrate the mammalian skin intact. Each transferosome consists of at least one inner aqueous compartment, which is surrounded by a lipid bilayer with specially tailored properties, due to the incorporation of "edge activators" into the vesicular membrane. Surfactants such as sodium cholate, sodium deoxycholate, span 80 and Tween 80, have been used as edge activators. It was suggested that transfersomes could respond to external stress by rapid shape transformations requiring low energy. These novel carriers are applied in the form of semi-dilute suspension, without occlusion. Due to their deformability, transfersomes are good candidates for the non-invasive delivery of small, medium and large sized drugs. They have been used as drug carriers for a range of small molecules, peptides, proteins and vaccines, both in vitro and in vivo. Transfersomes penetrate through the pores of stratum corneum which are smaller than its size and get into the underlying viable skin in intact form. This is because of its deformable nature. Multiliter quantities of sterile, well-defined transfersomes containing drug can be and have been prepared relatively easily. Materials commonly used for the preparation of transferosomes are phospholipids (soya phosphatidyl choline, egg phosphatidyl choline), surfactant (Tween 80, sodium cholate) for providing flexibility, alcohol (ethanol, methanol) as a solvent, dye for confocal scanning laser microscopy (CSLM) and buffering agent (saline phosphate buffer Ph 7.4), as a hydrating medium.

Silent features of transfersomes

· Transferosomes possess an infrastructure consisting of hydrophobic and hydrophilic moieties together and as a result can accommodate drug molecules with wide range of solubility.

· This high deformability gives better penetration of intact vesicles.

· Transfersomes can deform and pass through narrow constriction (from 5 to 10 times less than their own diameter) without measurable loss.

· They can act as a carrier for low as well as high molecular weight drugs e.g. analgesic, anesthetic, corticosteroids, sex hormone, anticancer, insulin, gap junction protein, and albumin.

· They are biocompatible and biodegradable as they are made from natural phospholipids similar to liposomes.

· They have high entrapment efficiency, in case of lipophilic drug near to 90%.

· They protect the encapsulated drug from metabolic degradation.

· They act as depot, releasing their contents slowly and gradually.

· They can be used for both systemic as well as topical delivery of drug.

· Easy to scale up, as procedure is simple, do not involve lengthy procedure and unnecessary use or pharmaceutically unacceptable additives.

Advantages

· Delivery of peptides by transfersomes provides a very successful means for the non-invasive therapeutic use of such large molecular weight drugs on the skin.

· They are used as a carrier for protein and peptides like insulin, bovine serum albumin, vaccines, etc. The delivery of these large biogenic molecules into the body is difficult. When given orally, they are completely degraded in the GI tract.

Limitations of transfersomes

· Transfersomes are chemically unstable because of their predisposition to oxidative degradation.

· Purity of natural phospholipids is another criteria militating against adoption of transfersomes as drug delivery vehicles.

· Transfersomes formulations are expensive.

Colloidosomes

Colloidosomes are the hollow shell microcapsules consisting of coagulated or fused particles at interface of emulsion droplets. Colloidosomes have exciting potential applications in controlled release of drugs, proteins, vitamins as well as in cosmetics and food supplements. Colloidosomes have a great encapsulation efficacy with a wide control over size, permeability, mechanical strength and compatibility. Colloidosomes is a novel class of microcapsules whose shell consists of coagulated or fused colloid particles at interface of emulsion droplets. The particles self assemble on the surface of droplets in order to minimize the total interfacial energy forming colloidosomes. Such structures were produced for first time by templating latex particles adsorbed on the surface of octanolin- water emulsion drops and subsequent removal of oil after fusing the particles monolayers. Similar structures have also been obtained by templating water-in-oil emulsions and templated solid nanoparticles on the surface of solid sacrificial microparticles based on electrostatic attraction and layer by layer assembly of multilayer shells consisting of alternating positively and negatively charged nanoparticles or polyelectrolytes. The final hollow shells are obtained by removal of central, sacrificial colloidal particles. Colloidosomes assemble polymer latex colloidal particles into shells around water-in-oil emulsion drops followed by partial fusion of shell and centrifugal transfer into water to yield stable capsules in which the shell permeability can be controlled by adjustment of partial fusion conditions. Hairy colloidosomes whose shell consists of microrod particles are designed and novel colloidosome capsules that consist of aqueous gel core and shells of polymeric microrods are fabricated. This has been achieved by templating water-in-oil emulsions stabilized by rod like particles followed by gelling of the aqueous phase, dissolution of oil phase in ethanol and redispersion of obtained colloidosome microcapsules in water.

Advantages

· Control of the size allows flexibility in applications and choice of encapsulated materials.

· Colloidosome membranes offer great potential in controlling the permeability of the entrapped species and allow the selective and time release.

· Control of the mechanical strength allows the yield stress to be adjusted to withstand varying of mechanical loads and to enable release by defined shear rates.

Herbosomes

The term ‘herbo’ means plant, while ‘some’ means cell like. Over the past century, phytochemical and phyto-pharmacological sciences established the compositions, biological activities and health promoting of numerous botanical products. Most of the biologically active constituents of plants are polar or water soluble molecules. However, water soluble phytoconstituents (like flavonoids, tannins, glycosidic aglycones etc) are poorly absorbed either due to their large molecular size which cannot be absorbed by passive diffusion, or due to their poor lipid solubility, severely limiting their ability to pass across the lipid rich biological membranes, resulting poor bioavailability. Phytomedicines, complex chemical mixtures prepared from plants, have been used for health maintenance since ancient times. But many Phytomedicines are limited in their effectiveness because they are poorly absorbed when taken by mouth. Herbosomes are also often known as phytosomes.

Herbosomes exhibit better pharmacokinetic and pharmacodynamic profile than conventional herbal extracts. Molecular layer consisting of PC and other phospholipids provides a continuous matrix into which the proteins insert.

Advantages

· It enhances the absorption of lipid insoluble polar phytoconstituents through oral as well as topical route showing better bioavailability, hence significantly greater therapeutic benefit.

· As the absorption of active constituent(s) is improved, its dose requirement is also reduced.

· Phosphatidylcholine used in preparation of herbosomes, besides acting as a carrier also acts as a hepatoprotective, hence giving the synergistic effect when hepatoprotective substances are employed.

· Herbosome permeates the non lipophilic botanical extract to be better absorbed in intestinal lumen.

· Unlike liposome, chemical bonds are formed between phosphatidylcholine molecule and phytoconstituents, so the herbosomes show better stability profile.

Sphingosomes

Sphingosomes are vesicular drug delivery systems in which an aqueous volume is entirely enclosed with sphingolipid bilayer membranes. Sphingolipids are developed as bioeffector molecules, which regulate cell growth, proliferation and anti-cancer therapeutics. Sphingosomes have become an enhanced area of interest because of their applicability in improving the in vivo delivery of various chemotherapeutic agents, biological macromolecules and diagnostics.

Liposome stability problems are of course much more severe so it is very important task to improve the liposomal stability. Liposomal phospholipid can undergo chemical degradation such as oxidation and hydrolysis either as a result of these changes or otherwise liposome maintained in aqueous suspension may aggregate, fuse, or leak their content. Hydrolysis of ester linkage will slow at pH value close to neutral. The hydrolysis may be avoided altogether by use of lipid which contains ether amide linkage instead of ester linkage (such are found in sphingolipid) or phospholipid derivatives with the 2- ester linkage replaced by carbomoyloxy function. Thus sphingolipid are nowadays used for the preparation of stable liposomes known as sphingosomes. Sphingosome may be defined as “concentric, bilayered vesicle in which an aqueous volume is entirely enclosed by a membranous lipid bilayer mainly composed of natural or synthetic sphingolipid. Sphingosomes are administered in many ways these include parenteral route of administration such as intravenous, intramuscular, subcutaneous, and intra-arterial. Generally it will be administered intravenous or some cases by inhalation. Often it will be administered into a large central vein, such as the superior vena cava and inferior vena cava to allow highly concentrated solution to be administered into large volume and flow vessels. Sphingosomes may be administered orally or transdermally. In simple way we can say sphingosome is liposome which is composed of sphingolipid.

Advantages

· Provide selective passive targeting to tumour tissue.

· Increase efficacy and therapeutic index.

· Increase stability via encapsulation.

· Reduction in toxicity of the encapsulated agents.

· Improve pharmacokinetic effect (increase circulation time).

· Flexibility to couple with site-specific ligands to achieve active targeting.

Cubosomes

Bicontinuous cubic liquid crystalline materials are active ingredients because they give the unique structural ends to controlled release applications. Amphiphilic molecules form bicontinuous water and oil channels, where “bicontinuous” refers to two distinct (continuous, but non-intersecting) hydrophilic regions separated by the bilayer. Cubosomes are discrete, sub micron, nanostructured particles of bicontinuous cubic liquid crystalline phase. Cubosomes possess the same microstructure as the parent cubic phase but have much larger specific surface area and their dispersions have much lower viscosity than the bulk cubic phase. The ability of cubic phases to exist as discrete dispersed colloidal particles or cubosomes is perhaps the most intriguing. Whereas most concentrated surfactants that form cubic liquid crystals lose these phases to micelle formation at high dilutions, a few surfactants have optimal water insolubility. Their cubic phases exist in equilibrium with excess water and can be dispersed to form cubosomes. Cubosomes are typically produced by high-energy dispersion of bulk cubic phase, followed by colloidal stabilization using polymeric surfactants. After formation of the cubosomes, the dispersion is formulated into a product and then applied to a substrate of interest, usually bodily tissue.

Advantages

· Cubic phase materials can be formed by simple combination of biologically compatible lipids and water and are thus well suited for use in treatments of skin, hair, and other body tissue.

· With respect to liposome, cubosome possesses a larger ratio between the bilayer area and the particle volume and a larger breaking resistance.

Coated vesicles

Improving the stability of vesicular systems is of great concern. A number of attempts have been made to improve the stability of vesicles by preparing polymerizable vesicles such as polymerizable liposomes. Increasing the circulation half-life of liposomes by coating of nonionic surfactant and by using polyethylene glycol. Recently, a method to produce stable, discrete, polymer-coated niosomal vesicles for controlled delivery of the contents has been reported. Among the various methods employed for increasing the stability of niosomes, microencapsulation technique has gained wide attention. Polymer coating of the vesicle can be achieved by interfacial polycondensation. The polymer-coated vesicles are slightly larger in size as compared to their uncoated counterparts. The release of drug from polymer-coated vesicles is regarded as compared to plain vesicles. This may be attributed to the effective double barrier produced by the polymeric coat. In order to obtain a stable and protective vesicular system, this system paves way for a newer dimension in vesicular carrier system stability.

Layerosomes

The layer-by-layer coating concept is one of the strategies used for the preparation or the stabilization of nanosystems. The Layerosomes are conventional liposomes coated with one or multiple layers of biocompatible polyelectrolytes in order to stabilise their structure. The formulation strategy is based on an alternative coating procedure of positive poly (lysine) (pLL) and negative poly (glutamic acid) (pGA) polypeptides on initially charged small unilamellar liposomes. The major drawback of liposomes is their instability during storage or in biological media which is related to surface properties. This surface modification stabilized the structure of the liposomes and led to stable drug delivery systems. Oral administration or their incorporation in biomaterials are among potential fields of application. Thus, the concept of layerosomes has brought forward the stable nanosystem.

Ufosomes

The formation of fatty acid vesicles is named "ufosomes," ufosomes are unsaturated fatty acid liposomes. Fatty acid vesicles are colloidal suspensions of closed lipid bilayers that are composed of fatty acids and their ionized species (soap). They are observed in a small region within the fatty acid-soap-water ternary phase diagram above the chain melting temperature of the corresponding fatty acid-soap mixture. Fatty acid vesicles always contain two types of amphiphiles, the nonionized neutral form and the ionized form (the negatively charged soap). The ratio of nonionized neutral form and the ionized form is critical for the vesicle stability. Fatty acid vesicles are actually mixed "fatty acid/soap vesicles". Ufosome membranes are much more stabilized in comparison to liposomes.

Approaches for improvement of vesicular system: Pro-vesicular Drug Delivery ^{8, 9}

Pro vesicular drug delivery system developed to overcome the stability problems associated with vesicular drug delivery systems composed of water soluble porous powder as a carrier drug is dissolved in organic solvent to produce free-flowing granular product. It can avoid many of the problems associated with aqueous vesicular dispersions. Types of provesicular drug delivery systems are

· Pro-liposomes

· Pro-niosomes.

Drug	Route of administration	Application	Targeted diseases
Amphotericin-B	Oral delivery	Ergosterol membrane	Mycotic infection
Pentoxyfylline	Pulmonary delivery	Phosphodiesterase	Asthma
Levonogesterol	Transdermal	Rhamnose receptor	Skin disorder
Ibuprofen	Oral delivery	Chemoreceptor, free nerve ending	Rheumatoid arthritis

Vesicular system	Stability consideration
Liposomes	Stability issue of liposomes remains an area which is surrounded by a number of problems due the formation of ice crystals in liposomes, the subsequent instability of bilayers leads to the leakage of entrapped material. The physical instability is another problem faced by liposomes. The oxidation of cholesterol and phospholipids also leads to the formulation instability. Chemical instability primarily indicates hydrolysis and oxidation of lipids.
Niosomes	The niosomes even being superior than liposomes have various stability problems associated with them such as physical stability of fusion, aggregation, sedimentation and leakage on storage. The hydrolysis of encapsulated drugs which limits the shelf life of the dispersion is also an issue for niosomes.
Pharmacosomes	Entrapment efficiency is not only high but predetermined, because drug itself in conjugation with lipids forms vesicles. It has no time-consuming steps for removing the free, unentrapped drug from the formulation. Since the drug is covalently linked, loss due to leakage of drug, does not take place.
Ethosomes	Ethosomes has initiated a new area in vesicular research for transdermal drug delivery which can provide better skin permeation and stability than liposomes. Application of ethosomes provides the advantages such as improved entrapment and physical stability.
Transferosomes	Transferosomes are chemically unstable because of their predisposition to oxidative degradation. Purity of natural phospholipids is another criterion militating against stability of transferosomes as drug delivery vehicles.
Colloidosomes	Major problem in the colloidosome manufacture is the poor yield of particles. If the shell locking is inefficient then the colloidosomes simply coalesce and fall apart on transfer into water. In addition a large proportion of the colloidosomes seem to be lost on the transfer from organic to water media.
Herbosomes	Chemical bonds are formed between phosphatidylcholine molecule and phytoconstituents, so the herbosomes show better stability profile with appreciable drug entrapment.
Sphingosomes	Higher cost of sphingolipid hinders the preparation and use of these vesicular systems. They show better stability as compared to liposomes though they have low entrapment efficacy. Sphingosomes solve the major drawback of vesicle system (liposomes, niosomes) like less stability, less in vivo circulation time, low tumour loading efficacy in case of cancer therapy.
Cubosomes	Cubosomes posses the simple production procedure and have better chemico-physical stability. They are the good option with many advantages over liposomes, manufacture of cubosomes on a large scale embodied difficulty because of their viscosity.
Vesosomes	Nested bilayer compartment in vitro via the ‘interdigitated’ bilayer phase formed by adding ethanol to a variety of saturated lipids.
Archeaosomes	Vesicle composed of glycolipids of Achaea with potent adjuvant activity.
Proteosomes	High molecular weight multi-subunit enzyme complexes with catalytic activity, which is specifically due to the assembly pattern of enzyme
Hemosomes	Haemoglobin containing liposome engineered by immobilizing haemoglobin with polymerizable phospholipids.
Erythrosomes	Liposomal system in which chemically cross linked human erythrocytes cytoskeletons are used as support to which lipid bilayer is coated.
Photosomes	Photolyase encapsulated in liposome which releases the contents by photo triggered charges in membrane permeability characteristics.
Genosomes	Artificial micro molecular complexes for functional gene transfer. Cationic lipids are most suitable because they posses high biodegradability and stability in blood stream.
Virosomes	Liposome spiked with virus glycoprotein, incorporated into the liposomal bilayer based on retrovirus derived lipids.
Ufasomes	Vesicles enclosed by fatty acids obtained from long chain fatty acids (oleic and linoleic acid) by mechanical agitation of evaporated films in the presence of buffer solutions.
Cryptosomes	Lipid vesicles with a surface code composed of PC and suitable polyoxyethylene derivative of phosphatidyl ethanolamine.
Discomes	Noisome solubilised with no-ionic surfactant solution( Polyoxyethylene cetyl ether class)
Enzymosomes	Liposomal constructs engineered to provide a mini bioenvironment in which enzymes are covalently immobilized or coupled to the surface of liposomes.