Review Article | Open Access
Shikha Jain, Vikas Jain, S. C. Mahajan, "Lipid Based Vesicular Drug Delivery Systems", Advances in Pharmaceutics, vol. 2014, Article ID 574673, 12 pages, 2014. https://doi.org/10.1155/2014/574673
Lipid Based Vesicular Drug Delivery Systems
Vesicular drug delivery system can be defined as highly ordered assemblies consisting of one or more concentric bilayers formed as a result of self-assembling of amphiphilic building blocks in presence of water. Vesicular drug delivery systems are particularly important for targeted delivery of drugs because of their ability to localize the activity of drug at the site or organ of action thereby lowering its concentration at the other sites in body. Vesicular drug delivery system sustains drug action at a predetermined rate, relatively constant (zero order kinetics), efficient drug level in the body, and simultaneously minimizes the undesirable side effects. It can also localize drug action in the diseased tissue or organ by targeted drug delivery using carriers or chemical derivatization. Different types of pharmaceutical carriers such as polymeric micelles, particulate systems, and macro- and micromolecules are presented in the form of novel drug delivery system for targeted delivery of drugs. Particulate type carrier also known as colloidal carrier system, includes lipid particles, micro- and nanoparticles, micro- and nanospheres, polymeric micelles and vesicular systems like liposomes, sphingosomes, niosomes, transfersomes, aquasomes, ufasomes, and so forth.
In the past few decades, considerable attention has been paid to the development of novel drug delivery system. The novel drug delivery systems aim to fulfill two prerequisites; that is, it delivers the drug at a rate directed by the needs of the body, over the period of treatment, and it carries the drug directly to the inflamed tissues and/or organ. Conventional delivery systems including prolonged release dosage forms are unable to meet none of these. Novel drug delivery system sustains drug action at a predetermined rate, relatively constant (zero order kinetics), efficient drug level in the body, and simultaneously minimizes the undesirable side effects. It can also localize drug action in the diseased tissue or organ by targeted drug delivery using carriers or chemical derivatization. Different types of pharmaceutical carriers such as polymeric micelles, particulate systems, and macro- and micromolecules are presented in the form of novel drug delivery system for targeted delivery of drugs. Particulate type carrier, also known as colloidal carrier system, includes lipid particles, micro- and nanoparticles, micro- and nanospheres, polymeric micelles, and vesicular systems like liposomes, sphingosomes, niosomes, transfersomes, aquasomes, ufasomes, and so forth.
1.1. Lipid Based Vesicular Drug Delivery System
Vesicular drug delivery system can be defined as highly ordered assemblies consisting of one or more concentric bilayers formed as a result of self-assembling of amphiphilic building blocks in presence of water. The biologic origin of lipid based vesicles was first reported by Bingham in 1965 and hence was named as Bingham Bodies. Vesicular drug delivery systems are particularly important for targeted delivery of drugs because of their ability to localize the activity of drug at the site or organ of action thereby lowering its concentration at the other sites in body.
1.1.1. Advantages of Vesicular Drug Delivery System
(i)Both hydrophilic and hydrophobic drugs can be easily encapsulated.(ii)Bioavailability of drugs can also be improved.(iii)Elimination of rapidly metabolizable drug can be delayed.(iv)Circulation life time of drugs in the body can be prolonged.(v)Targeted delivery of drugs can often be achieved.(vi)Stability issues of liable drugs can be resolved.(vii)Toxicity issues of certain drugs can often be resolved.
1.2. Liposomes as Vesicular Drug Delivery System
Liposomes are colloidal, concentric bilayered vesicles where aqueous compartment is entirely enclosed by a bilayer membrane, mainly composed of natural or synthetic lipids. The essential components of liposomal drug delivery system include phospholipids (mainly phosphatidylcholine) and cholesterol where cholesterol acts as a fluidity buffer. Although cholesterol do not participate in bilayer formation, it can be added to phosphatidylcholine up to 1 : 1 or even 2 : 1 molar ratio of cholesterol to phosphatidylcholine. Liposomes have gained much importance as potential drug carrier systems for targeted drug delivery . Different researches on liposomes as vesicular drug delivery system are presented in Table 1.
1.2.1. Advantages of Liposomes as Vesicular Drug Delivery System 
(i)Liposomes are suitable to deliver hydrophilic and lipophilic drugs.(ii)Improved stability, protects the encapsulated drug from environment.(iii)Reduced toxicity.(iv)Reduced exposure of sensitive tissues to toxic drugs and their metabolites.(v)Liposomes are suitable to deliver small molecular weight drugs as well as high molecular weight drugs.(vi)Target specific delivery can be achieved.(vii)Improved pharmacokinetic properties as reduced elimination and increased circulation life time.
1.2.2. Disadvantages of Liposomes as Vesicular Drug Delivery System
(i)Liposomes are leaky in nature leading to premature drug release.(ii)Poor encapsulation efficiency for hydrophilic drug.(iii)Liposomes are expensive.(iv)Liposomes possess short half-life.
1.3. New Eras of Vesicular Drug Delivery Systems
Requirement of cryogenic atmosphere for the handling of liposomes have prompted the use of nonionic surfactants for the preparation of vesicular drug delivery systems. This newly introduced vesicular drug delivery system was termed as niosome which consist of unilamellar or multilamellar vesicles. Niosomes, that is, non-ionic surfactant vesicles, are microscopic lamellar vesicles formed when nonionic surfactants (mainly of alkyl or dialkyl polyglycerol ether class) are added to cholesterol with subsequent hydration in aqueous media. Addition of cholesterol provides rigidity to the bilayer leading to the formation of less permeable niosomes. Addition of nonionic surfactants to niosomes increases the size of vesicles and provides charge to the vesicles and hence increases the entrapment efficiency of niosomes. Niosomes possess structure that is similar to liposomes and hence represent a promising drug delivery module. Niosomes are expected to be better drug carrier system than liposomes upon consideration of factors like cost, stability, entrapment efficiency, bioavailability, and so forth . Different researches on niosomes as vesicular drug delivery system are presented in Table 2.
(1) Advantages of Niosomes (i)Niosomes are relatively more stable.(ii)They do not require any special handling and storage condition.(iii)Niosomes are osmotically active.(iv)Niosomes can entrap drugs with wide range of solubility.(v)They can serve as a depot system to release the drug slowly as and when required.(vi)Niosomes are more flexible in design and structure than liposomes.(vii)They can increase oral, topical, and parenteral bioavailability of drugs.(viii)They improve the therapeutic performance of entrapped drug simply by restricting its effect to the target cells and by reducing the clearance of the drug.
Because of the fact that liposomes and niosomes have poor skin permeability, their permeable nature, and their aggregation and fusion in skin tissues, they are not suitable for transdermal delivery of drugs and hence lead to the development of new type of carriers called transfersomes in 1991 by Gregor Cevc. Transfersomes means carrying body and is derived from Latin word “Transferre” (meaning to carry across) and a Greek word “some” (meaning body). Thus transfersomes can be defined as ultradeformable, stress responsive, complex vesicles possessing an aqueous core surrounded by complex bilayer of lipids. These artificial vesicles are composed of one natural amphiphilic lipid (e.g., phosphatidylcholine, dipalmitoylphosphatidylcholine) and are supplemented by a bilayer softener, that is, biocompatible surfactant (e.g., sodium cholate, span 80, and tween 80). Presence of amphiphilic surfactants allows transfersomes to modify their membrane composition reversibly so as to penetrate through narrow skin pores . Different researches on transfersomes as vesicular drug delivery system are presented in Table 3.
(1) Advantages of Transfersomes . Since both hydrophilic and hydrophobic moieties are present in transfersomes, they can accommodate drugs with wide range of solubility.(i)They are so deformable that they can penetrate even through the narrow pores of skin without measurable loss.(ii)Both low and high molecular weight drugs can be entrapped efficiently.(iii)They protect the encapsulated drug from enzymatic, metabolic degradation.(iv)They can be used for topical as well as systemic delivery of drugs.(v)They can act as a depot formulation to release the contained drug in controlled manner.
(2) Disadvantages of Transfersomes(i)They are chemically unstable.(ii)Purity of phospholipids is another important criterion to be considered.(iii)They are expensive.
Administration of bioactive molecules in their active state has been a challenge to the pharmaceutical as well as biotechnological industries. Drug associated challenges such as suitable route and site of drug delivery, chemical and physical instability, poor bioavailability, and potentially serious side effects of these bioengineered molecules (peptide, protein, hormones, antigens, and genes) are some potential limitations for successful formulation of these biomolecules. The combination of biotechnology and nanotechnology (i.e., nanobiotechnology) has proposed a new approach as a solution to their formulation problem in the form of aquasomes.
Aquasomes are like “bodies of water" and can be defined as trilayered self-assembled nanostructures comprising a solid phase nanocrystalline core which is coated with an oligomeric film (made up of carbohydrate) on which biochemically active molecules are adsorbed with or without modification. Aquasomes are also known as ceramic nanoparticles. The solid core provides the structural stability, at the same time as the products of carbohydrate coating against dehydration, and stabilizes the biochemically active molecules, and so forth. The nanocrystalline core comprises polymers such as albumin, gelatin, or acrylate or Ceramic such as diamond particles, brushite (calcium phosphate), and tin oxide. Coating materials commonly used are sucrose, cellobiose, trehalose, pyridoxal 5 phosphate, chitosan, citrate, and so forth. Aquasomes are widely utilized for the delivery of insulin, hemoglobin, and enzymes like serratiopeptidase . Different researches on aquasomes as vesicular drug delivery system are presented in Table 4.
(1) Advantages of Aquasomes (i)Aquasomes preserves the conformational integrity and biochemical stability of bioactive molecules.(ii)Because of their size and structure stability, aquasomes avoid reticuloendothelial clearance or degradation by other environmental challenges.(iii)Aquasomes exhibit physical properties of colloids.(iv)Since aquasomal suspension contains colloidal range biodegradable nanoparticles, they are more concentrated in liver and muscles.(v)Since the drug is absorbed on to the surface of the system without further surface modification as in case of insulin and antigen delivery, they may not find any difficulty in receptor recognition on the active site so that the pharmacological or biological activity can be achieved immediately.
Colloidosomes are the advanced drug delivery system for the efficient delivery of proteins, vitamins, and food supplements. They are hollow shell microcapsules consisting of coagulated or fused particles at the interface of emulsion droplets. They can be prepared by introducing colloidal particles into the continuous phase of a water-in-oil emulsion where the particles self-assemble at the interface between the two immiscible liquid phases and form a colloidal shell structure. Subsequently, the colloidal shell structures, hydrated by the water droplets dispersed in the oil phase, are transferred to an aqueous phase either by centrifugation or repeated washing. This methodology has been used to create colloidosomes with particles ranging from 5 nm to several microns in diameter .
(1) Advantages of Colloidosomes (i)Controlled size of colloidosomes provides flexibility in applications and choice of encapsulated material.(ii)They possess better potential in controlling the permeability of the entrapped species and allow the selective and time release.(iii)Colloidosomes are easy to construct.(iv)Colloidosomes have good mechanical strength so that yield stress can be adjusted to withstand mechanical load and to enable release by defined shear rates.(v)Fragile and sensitive materials such as biomolecules and cells can be easily encapsulated.
(2) Disadvantages of Colloidosomes(i)They have poor yield.(ii)When colloidosomes are transferred from organic to aqueous media, large proportion of colloidosomes is lost.(iii)Insufficient locking of shell leads to coalescence of colloidosomes.
In presence of polar solvents, the hydrophobic region of amphiphilic molecules self-assembles into an array of thermodynamically stable liquid crystalline phases with lengths on nanometer scale. These liquid crystalline phases possess sufficient degree of molecular orientation and structural symmetry. One example is bicontinuous cubic liquid crystalline phase.
Bicontinuous cubic phases are extremely viscous, optically isotropic, and solid, similar to liquid crystalline substance with cubic crystallographic symmetry, and consist of two divided, continuous but nonintersecting hydrophilic regions divided by a lipid bilayer in to a periodic minimal surface with zero curvature. This bicontinuous nature of such cubic phases differentiates them from the micellar or discontinuous cubic containing micelles packed in cubic symmetry. One of the important properties these cubic phases have is their ability to be dispersed in to particles, termed as cubosomes. They 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 can be formulated as a product and then applied to a bodily tissue. The term “cubosomes” was given by Larsson, which reflects the cubic molecular crystallography and similarity to liposomes . Different researches on cubosomes as vesicular drug delivery system are presented in Table 5.
(1) Advantages of Cubosomes (i)Cubosomes have the potential for targeted release and controlled release of bioactive agents.(ii)Hydrophilic, hydrophobic, and amphiphilic drugs can easily be encapsulated into cubosomes.(iii)Cubosomes are easy to be prepared.(iv)Since the lipids used in the formulation of cubosomes are biodegradable in nature, cubosomes are biodegradable.(v)Cubic crystalline structure and high internal surface area allow high drug payloads.(vi)Cubic phases are more bioadhesive in nature, so that they can be conveniently used in topical and mucosal delivery of drugs.
With liposomes, there are certain issues related with their stability including oxidation, hydrolysis, degradation, leaching, sedimentation, drug aggregation, and so forth. Therefore, to improve stability the researchers have led us to the development of Sphingosomes [13, 14].
Sphingosomes can be defined as colloidal, concentric bilayered vesicles where aqueous compartment is entirely enclosed by a bilayer membrane, mainly composed of natural or synthetic sphingolipids; that is, sphingosomes are liposomes that are composed of sphingolipids. Sphingosomes consist of sphingolipid (sphingomyelin) and cholesterol at acidic intraliposomal pH ratio of sphingomyelin and cholesterol varying in the range of 75/25 mol%/mol% (55/45 mol%/mol% most preferably). Sphingosomes is more stable than the phospholipid liposome because of the following.(i)Sphingolipid are built up by only amide and ether linkage. They are more resistant to hydrolysis than ester linkage of lecithin.(ii)They also contain a smaller amount of double bonds then lecithin and thus less subjected to rancidity.(iii)They also absorb a smaller amount oil then lecithin that in consequence change in geometry and diameter.
The major sphingolipids that have been used in the formulation of sphingosomes include Sphinganines, Hexadecasphinganine, Lysosphingomyelins, and lysoglycosphingolipids, N-Acylsphingosines, Gangliosides, Glucuronosphingolipids, Phosphoglycosphingolipids, and so forth.
(1) Advantages of Sphingosomes (i)Sphingosomes have better drug retention characteristics.(ii)They can be administered by subcutaneous, intravenous, intra-arterial, intramuscular, oral, and transdermal routes of drug administration and so forth.(iii)They provide selective passive targeting to tumor tissue.(iv)Sphingosomes increase efficacy and therapeutic index of the encapsulated drug.(v)Stability is increased via encapsulation.(vi)Toxicity of the encapsulated drug is reduced.(vii)Sphingosomes improve pharmacokinetics of the encapsulated drug simply by increasing the circulation time.(viii)Design of sphingosomes is so flexible to allow coupling with site specific ligands to achieve active targeting.
(2) Disadvantages of Sphingosomes(i)Since sphingolipids are expensive, sphingosomes are not economic.(ii)Sphingosomes have poor entrapment efficiency.
1.3.7. Ufasomes 
Since topical route of administration has lower risk of systemic side effects, topical treatment appears to be most favorable route of administration, although the stratum corneum restricts the penetration of drugs into viable skin. Ufasomes have been developed to enhance penetration of drug into viable skin through stratumcorneum. Ufasomes containing lipid carriers that attached to the skin surface and allows lipid exchange between the outermost layers of the stratumcorneum. This carrier system appears to be promising for efficient delivery of drugs. Besides liposomes and niosomes, ufasomes have been developed for their potential for topical/transdermal delivery of drugs, proteins, peptides, hormones, and so forth. The formation of fatty acid vesicles was first reported by Gebicki and Hicks in 1973 and the vesicles formed were initially named “ufasomes,” reflecting unsaturated fatty acid liposomes. Ufasomes, that is, unsaturated fatty acid vesicles, are suspensions of closed lipid bilayers that are composed of fatty acids and ionic surfactants. The pH range of ufasomal suspension varies from 7 to 9. In ufasomes, fatty acid molecules assemble themselves in a manner that their hydrocarbon tails are directed toward the inner side of the membrane and the carboxyl groups remains in contact with water.
(1) Advantages of Ufasomes(i)Ufasomes are more stable than liposomes.(ii)They have better entrapment efficiency for both hydrophilic and hydrophobic drugs.(iii)Ufasomes are cheaper than liposomes.
2. Expert Opinion
Vesicular drug delivery systems are now useful in various scientific fields. In recent era these systems have become one of the vast and major delivery systems due to its efficient properties and functions like selective targeting. However, the pharmacokinetics of drugs is in research for making these drug delivery systems most valuable. Also the mechanism of action of this system is in its complete progress.
Sphingosomes are bilayered vesicles that have an aqueous volume completely covered by membrane lipid bilayer. This bilayer is formed of natural or synthetic sphingolipid. Due to their flexibility in size and composition, they have been developed for encapsulating chemotherapeutic agent, biological macromolecule, and diagnostics.
Aquasomes are responsible for preserving the structural integrity of proteins including hemoglobin and insulin, thus promoting a better therapeutic effect. They are the self-assembling surface-modified nanocrystalline ceramic cores. These preparations have been characterised for immunological response and may be used as immunoadjuvants.
Transfersomes have large molecules like peptides, hormones, and antibiotics. Because of these properties, they have their wide role in the drug delivery systems. Also for the drugs with poor penetration due to undesirable physiological characters and drugs for faster targeted actions, they have been widely used.
Colloidosomes have efficient results and properties for release of drugs, proteins, vitamins, and cosmetics and food supplements. Due to this property the colloidal drug delivery systems have changed the terms of treatment and diagnosis. They have wide control over size, permeability, mechanical strength, and compatibility.
Cubic liquid crystals are transparent and isotropic phases that are physically stable in excess water representing a unique system for the production of pharmaceutical dosage forms. Cubosome nanoparticles formed from cubic liquid crystalline phases are a unique and intriguing self-assembled material with enormous potential in areas as diverse as medicine, materials science, and consumer products.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
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