Lipid Nanoformulations for Oral Delivery of Bioactives: an Overview

Send Orders for Reprints to [email protected] Current Drug Therapy, 2014, 9, 35-46 35 Lipid Nanoformulations for Oral Delivery of Bioactives: An Overview

Ranjana Gupta1, Anant Agrawal1, Md. Meraj Anjum2, Harinath Dwivedi1, Koshy M. Kymonil1 2, and Shubhini A. Saraf *

1Faculty of Pharmacy, Babu Banarasi Das National Institute of Technology and Management, Lucknow, India; 2Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India

Abstract: Oral drug delivery has always been considered the preferred route of drug administration. Nano-formulations are now constantly being researched for better absorption, higher bioavailability and greater therapeutic efficacy. Lipid based nanoformulations have found much favour with the formulation scientist due to their relatively higher safety profile and enhancement of bioavailability. These delivery systems are also able to protect the bioactives or drugs from the vagaries of the gastrointestinal tract. They also aid in the absorption of hydrophobic drugs which are entrapped in lipid matrices. Lipid excipients have been known to reduce efflux which is P-glycoprotein mediated and also to increase the bioavailability of bioactives which are given through the oral route. In the last 20 years, about a thousand articles and reviews about oral lipid carriers have been reported. Many dosage forms have been made by modifying liposome, sometimes to overcome a disadvantage and at other times to modify the dosage form in such a manner so as to suit the requirement of the drug molecules. Various other lipidic drug delivery systems also exist which are not vesicular but being made of lipids, are equally useful for delivering lipophilic drugs. Although a Lipid Formulation Classification System exists, but there is no exhaustive review which discusses the entire lipid based, oral nanoformulations. The present review envisages discussing the various types of oral, lipid, nanosized, delivery systems available, so that an insight is gained into all these carriers, and the formulation scientist can make a judicious decision regarding choice of a lipid based carrier. Keywords: Drug delivery, lipoidal, lipophilic, nanoparticles, vesicular.

INTRODUCTION Lipid excipients have been known to reducePgp-mediated efflux and also to increase bioavailability of orally administered Lipid-based drug delivery systems (LBDDS) have bioactives. been established for the enhancement of bioavailability of highly lipophilic drugs. LBDDS are composed of lipids Huge strides have been taken in the field of lipid drug (solid lipid or liquid lipid), surfactants/co-surfactants, and delivery since its inception in 1965, to deliver drugs [7], solvents. The formulation scientist makes a decision protein, peptide and even gene delivery [8]. Liposomes were regarding choice of the excipients based on the desired first discovered by A.D. Bangham in the early 1960s [9, 10]. physical, chemical and biological properties required from Any formulation can be called successfully only when it the formulation [1, 2]. Excipients used for lipid based oral gains commercial importance and is marketed. A number of formulation have been extensively reviewed [3-5]. When liposomal formulations are available in the market with certain suitable changes are made to the reaction / process many of them in the clinical trials stage [11]. As compared to conditions like changes in temperature / pressure / pH the the non-vesicular systems, lipoidal vesicular systems such as lipidic excipients self-organize in different supramolecular ethosomes and invasomes can significantly improve the arrangements. The lipid bilayer structure which encases an topical delivery of water soluble drugs [12]. The potential of aqueous environment within it is called a vesicle or sac and lipidic drug delivery has not been fully realized due to is one of the most researched about drug delivery systems several drawbacks. Some of them are, low lipophilic drug [6]. loading capacity, burst release kinetics, degradation in low pH conditions and due to the action of sodium taurocholate, When administered orally, lipid based delivery is various types of lipases and so on [13,14]. advantageous as lipophilic drugs are solubilized in a lipid which could often be physiologically easily transported and These are the shortcomings of lipoidal delivery systems, absorbed through the intestine. These delivery systems are but can be overcome and can also be used to advantage, also able to protect the bioactives or drugs from the vagaries when the above mentioned phenomena are properly of the gastrointestinal tract. They also aid in the absorption understood and are used for better absorptivity of drugs [15]. of hydrophobic drugs which are entrapped in lipid matrices. A major disadvantage of liposomes for parenteral

delivery is their inherent chemical and physical instability.

*Address correspondence to this author at the Department of Pharmaceutical To overcome the drawbacks of liposomes, various kinds of Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India; lipoidal carriers and modified liposomes have been Tel: +91 522 2998129; E-mail: [email protected] developed as carriers (Fig. 1). For the improvement of

Fig. (1). Schematics of different types of oral lipid based carriers for drug delivery. stability, aspasomes were prepared using ascorbyl palmitate visualized as small droplets of water being protected from [16], to enhance the permeation of drug by transdermal coalescing with the neighboring similar structure due to the delivery ethosomes were prepared [17], to enhance the presence of lipid layer(s), in the form of an external sheath organoleptic appeal and presentation of a cosmetics, various covering each of these droplets [23]. Liposomes are formed type of novel drug delivery carriers such as liposomes, with the help of external energy (mechanical dispersion, phytosomes, ethosomes, pharmacosomes, microemulsions solvent dispersion and detergent removal). The main and nanocrystals have been discussed [18, 19]. component of liposome membranes are phospholipids (e.g. phosphotidylcholine, phophotidylserine and cholesterol etc.) In the last 20 years, about a thousand articles and reviews and amphiphiles [24]. A lot of work has been done to study about oral lipid carriers have been reported. Due to the the mechanics of how hydrophilic or hydrophobic drugs can numerous advantages many such formulations have come to be retained within these structures, and the factors which the market. A lot of literature is available regarding the determine their particle size, stability and so on [25]. Zhang material, formulation methods and evaluation of lipid based et al. investigated flexible liposomes as a potential oral drug oral delivery systems [20-22]. delivery system. Curcumin loaded silica-coated flexible This paper envisages discussing the various types of oral liposomes were prepared to enhance the bioavailability of lipid delivery systems available, so that an insight is gained curcumin and it was found that bioavailability is 7.76 fold into all these carriers, and the formulation scientist can make higher than that of curcumin suspensionsconfirming that a judicious decision regarding choice of a lipid based carrier. improved bioavailability was possible through such delivery systems [26]. Recent studies revealed improved liposomal Liposomes encapsulation and stability in heat processed food containing These are, hollow, lipidic, single or bilayered structures peptides [27]. Liposomes with phosphatidy lethanol as a enclosed within an aqueous environment. They can be carrier for oral delivery of insulin, has also been studied. Lipid Nanoformulations for Oral Delivery of Bioactives: An Overview Current Drug Therapy, 2014, Vol. 9, No. 1 37

Many of these liposome formulations have been patented Nanostructured Lipid Carriers (NLCs) and have also found their way into the market. Liposomal NLCs are advanced lipid nanoparticles which are the antracyclines appeared on the market al.most a decade ago next generation of SLNs. They are able to alleviate [28]. Oral vaccine delivery through liposomes has also been limitations like limited drug payload, polymorphic utilized for better patient compliance [29]. transitions. These consist of a mixture of solid lipid and Ethosomes liquid lipid. Due to differences in structures of solid and liquid lipid these cannot form a perfect crystal lattice and The ethosomes are vesicular carriers which comprise of hence the matrix contains imperfections which allows drug hydroalcoholic or hydro/alcoholic/glycolic phospholipids to be accommodated into the spaces created due to these and can be prepared by film hydration method [30] and hot imperfections [46]. melt method using magnetic stirrer, probe sonicator as well as high pressure homogenizer [31]. They necessarily contain Increased drug loading can be made possible by mixing a high quantity of alcohol which is capable of dissolving the both solid and liquid lipid (oils). Unlike other systems, NLCs lipid contained in the skin and thereby resulting in higher show high drug loading as well as physical stability. These penetrability. The higher alcoholic content also makes them can also be scaled up or used for the formulation of a flexible and thus makes them suited for delivery through conventional dosage form which is widely accepted by skin [32, 33]. patients (e.g: tablet, capsule, pellet etc.). NLCs dispersions can directly be filled into capsules because of their high It is anticipated that alcohol fluidizes the ethosomal lipids particle concentration and cream like consistency. Lipid and stratum corneum bilayer lipids for penetration enhancement nanoparticles can protect drug from unfavorable environment of drug. These delivery systems have been utilized for of gastrointestinal tract. NLCs show improved bioavailability topical and transdermal applications, largely because of their and increased plasma level after oral administration [47]. ability to squeeze through cells, but oral usage have also ® Nanaopearls are lipid nanoparticles which are used been reported. Ethosomes has also been used to enhance the commercially for oral bioavailability enhancement of drugs. oral bioavailability of poorly water soluble drugs [34]. Lipid Drug Conjugates (LDCs) Phytosomes The problem of low drug loading can be overcome with Phytosomes are advanced form of liposomes for the the use of lipid drug conjugate (LDCs) nanoparticles. The improvement of bioavailability of phytoconstituents. When insoluble drug is first conjugated with lipid, which could be polyphenolic phytoconstituents are complexed with through various mechanisms like covalent bonding, salt phosphatidylcholine in1:1 or 1:2 ratio, phytosomes can be formation and so on. The obtained LDCs can now be further formed [35, 36]. This is a patented technology of Indena, subjected to homogenization (high pressure or high shear) through which water soluble actives of plant origin can be to form nanoparticles. Olbrich et al. prepared LDCs delivered (mainly polyphenols) [37, 38]. Due to larger size and containing hydrophilic drug diminazene using high pressure hydrophilicity most of the phytoconstituents (anthocyanidins, homogenization technique [48, 49]. tannins, flavanoids and terpenoids) can penetrate lipoidal biological membranes [39]. Phytosomes are able to cross the The lipid drug conjugate nanoparticles-LDC® are a hydrophilic and hydrophobic environments to successfully registered product of PharmaSol and have been much reach the human circulation [40]. Phytosomes have researched for lipophilic drugs. The commercial scale up of been proven to be better suited for topical application than such products is easily possible. liposomes. Green tea extract was formulated into phytosomes ® Nanoemulsions (GreenSelect ). and these were converted into oral coated tablets by Pierro et al. (2009) Clinical trial on obese patients Nanoemulsions are either oil-in- water (o/w) or water- in- demonstrated that phytosome coated tablets were capable of oil (w/o) emulsions having mean droplet diameter ranging weight loss when administered orally to patients [41]. from 50-1000 nm. The average droplet diameter ranges between 100-500 nm. The nanoemulsions are also known as Solid Lipid Nanoparticles (SLNs) mini-emulsions, ultrafine emulsions or submicron emulsions. SLNs are the lipid nanoparticles which resemble polymeric These emulsions can generally be prepared in bulk by nanoparticles. These can be made of biocompatible lipids mixing the aqueous phase with the oil phase [50]. which remain in solid state at room temperature as well Nanoemulsions are considered as an important delivery as body temperature. When compared with other drug system as these display the following advantages: delivery systems the benefits of SLNs far outweigh the 1. Nanoemulsions possess very high surface area as well disadvantages. as higher free energy than conventional emulsions that Solid lipid nanoparticles (SLNs) have been widely used make them an effective delivery system. for the formulation of hydrophilic as well as hydrophobic 2. Problems associated with conventional emulsions actives [42, 43]. Other advantages of SLNs include controllable like creaming, flocculation, coalescence is avoided in drug release profile, decreased degradation velocity, easy to scale up, better physical stability etc. Solid lipid nanoparticles nanoemulsions. (SLNs) are capable of administering hydrophobic drugs 3. These are non-irritant and non-toxic; hence can be used through oral route because of their capacity to solubilize as topical preparations. these drugs when loaded in their lipid matrices, with the resulting improvement of the drug bioavailability [44, 45]. 38 Current Drug Therapy, 2014, Vol. 9, No. 1 Gupta et al.

4. Nanoemulsions can be used for drug targeting as well as adjuvant vaccine delivery vehicles. They offer the distinct controlled release formulations [51]. advantage of improved resistance to enzymatic, physical and chemical degradation over conventional liposomes. Archaea Pharmacosomes bacterial lipids consist of archaeol (diether) and/or caldarchaeol Pharmacosomes are self-assembled drug delivery (tetraether) core structures of regularly branched and fully systems of amphiphilic phospholipid complexes of drugs saturated phytanyl chains [65]. bearing active hydrogen that bind to phospholipids. Unilamellar vesicles (ULV) can be prepared by bath Pharmacosomes are colloidal dispersions of prodrugs and sonication followed by centrifugation of multilamellar lipid with improved biopharmaceutical properties [52]. vesicles (MLV) which are prepared by the film hydration These are prepared by hand-shaking and ether injection method of total polar lipid (TPL) of Archaea. As compared to method. Vaizoglu and Speiser (1986) first used the word conventional liposomes, archaeosomes made from the total ‘pharmacosomes’ to describe the amphiphilic phospholipid polar lipids of Methano sarcinamazei, Methanobacterium complexes prepared from drug-lipid conjugates with or espanolae or Thermoplasma acidophilum show stability without additional surfactants [53]. On dilution with water, properties and hence are suitable for oral drug delivery [66]. an amphiphilic prodrug gets converted to pharmacosomes, New type of adjuvants for archeosome (ARC) from depending upon the chemical structure of drug lipid complex Halorubrum tebenquichense non alkaliphilic strains elicited a [54, 55]. Pharmacosomes remove various shortcomings of strong and sustained primary antibody response, as well as vesicular drug delivery systems, such as low drug entrapment, improved specific humoral immunity after boosting with the leakage from carrier and short shelf life [56]. Imam et al. bare antigen [67]. Chen et al. explored the potential of (2009) reviewed various types of ocular dosage forms for the archaeosomes made of the polar lipid fraction E (PLFE) treatment of glaucoma [57]. Semalty et al. (2009) prepared extracted from Sulfolobus acidocaldarius exhibited stability pharmacosomes of diclofenac using phosphatidylcholine in the gastrointestinal milieu and therefore could be successfully (80%) and observed improvement in hydrophilicity of the utilized for oral delivery of bioactives [68]. Brown et al. prepared vesicles that displayed lower toxicity and better explored the potential of the polar lipid fraction E (PLFE) bioavailability [58]. The therapeutic performance of various isolated from the thermo acidophilic archaeo Sulfolobus drugs i.e., 1-β-D- arabino furanosyl cytosine, azidithymidine, acidocaldarius as carrier for drugs including genes, peptides, amoxicillin, cytarabine, isoniazid etc. has been improved by vaccines and siRNA. Currently archeosomes are being the pharmacosome approach [59, 60]. used as a carrier for promoting humoral and cell-mediated Vesosomes immune responses to M cell, MHC class- I cell and antigen- specific mucosal response in vaccinated persons [69-71]. These are new multi-compartment structures consisting of drug loaded liposomes encapsulated within another Hybrid Nanoparticles bilayer and are promising drug carriers with better retention Nanoparticles that contain two or more distinct and stability when compared with unilamellar liposomes. nanoparticles assembled in a functional structure that itself is The vesosomes are vesicles within the vesicle of liposome still of nanoscale dimensions [72]. Use of polymers along that rely on the phase behavior of lipid. Vesosomes have an with lipids in the formulation of hybrid nanoparticles may interlocking of saturated lipids. The lipoidal bilayers are flat, give an integrated system which shows the properties of both expanded, superficies, at lower temperatures which convert polymeric nanoparticles and lipid nanoparticles known as to unilamellar vesicles at higher temperature. Multiple drugs lipid polymer hybrid nanoparticles(LPHNs). LPHNs are can be encapsulated in vesosome compartment for avoiding solid, submicron particles made up of polymer and lipid pathogen resistance to a single drug.Vesosomes are slightly at the simplest level. The bio-mimetic characteristics of bigger particles with a size range of 0.1 µ to greater than lipids and structural advantage of polymer core may be 1.0µ [61]. It has been shown that by adding the triblock synergistically utilized to produce a theoretically superior copolymer to the inter-digitated sheets made from dipalmitol delivery system. LPHNs may be formulated by coating lipids phosphatidylcholine, the vesosomes are modified to a proper on polymer or polymer on lipid which makes core shell size for clinical use [62]. Vesosomes containing hollow gold structure. These core shell structured LPHNs show distinct nanoparticles and 6-carboxyflourescien in their interior advantages which are as follows: compartment have been confirmed by transmission electron microscopy and release the drug on trigger by NIR laser The polymeric core acts as a cytoskeleton that provides pulses in biological systems. Release time was affected by mechanical stability, controlled morphology, narrow size changes in the lipid composition of internal liposomes and distribution. not by the overall vesosomal structure. On evaluation of i The polymeric core provides mechanical strength, desired vesosomes for topical delivery of vaccines using tetanus particle size as well as size distribution [73, 74]. toxoid (TTx) as a model antigen, the systems elicited combined Th1 and Th2 immune responses [63]. ii Whenever the outer coat is lipoid, it enables a better Archaeosomes interaction with cell membrane. The coat has the potential to interact with a variety of ingredients/ Archaeosomes are liposomes made from the total polar organelles within the cell as well as extracellular [75]. lipids extracted from the membranes of Archaea lipid that iii Higher drug loading is possible, in comparison to most are chemically distinct from eukaryotic and prokaryotic vesicular systems like liposomes, in the case of LPHNs species [64]. Archaeosomes are self-assembled lipid vesicles [76, 77]. with greater stability for improved oral delivery and as Lipid Nanoformulations for Oral Delivery of Bioactives: An Overview Current Drug Therapy, 2014, Vol. 9, No. 1 39 iv Amphiphilic nature of lipids assists in the adsorption of being developed for treatment of gene delivery and various hydrophilic compounds on to the bilayer surface and tumors and CNS tumours in particular [86]. inclusion of the hydrophobic molecules within the hydrophobic lamellar region. This characteristic helps In vivo study suggests that phospholipid encapsulated LPHN encapsulate bioactives and also in delivering the nanosomes improve efficacy and reduce toxicity [87]. hydrophilic as well as hydrophobic drugs simultaneously Fluorogenic poly diacetylene nanosome based chips, array, [74]. film, fibers and strips are used for detection of protein- protein interaction, DNA and bacteria. Douliez et al. v Optimization of the core and shell may result in synthesized 1- 10 nm gold nanoparticles (Au-NP) which are controllable and sustained drug release profiles [78, 79]. stabilized by a layer of mercapto and/or hydroxyl bola Emulsomes palmitic acid–tetrabutyl ammonium salts (TBAOH) which form nanosomes in water. Nanosomes™ are the basic Emulsomes or solid-lipid nanoemulsions have a new type technology implemented in Nanosomin™, Equisomin™, of lipid assembly consisting of a hydrophobic core as in and the other Elsom Research cosmeceuticals. Elevated emulsion, but surrounded by phospholipid bilayer which is purity Phosphotidylcholine Nanosomes™ not only deliver the main characteristic of liposomes. These are 10-250 nm encapsulated ingredients to cells but they also deliver 0 particle of solid core or liquid crystalline phase at 25 C phosphatidylcholine (PC). This distinctive ability of elevated prepared by film hydration method. These can be purity PC Nanosomes™ renders them the most potent administered for the delivery of both fat soluble and water available tool in combating cellular aging [88, 89]. soluble drugs through several routes such as parenteral, oral, intranasal or topical. Emulsomes can be lyophilized by Layerosomes adding cryoprotectant such as sugars (glucose, sucrose, The layerosomes are conventional liposomes coated with lactose and trehalose), polysaccharides (dextrose, dextrin), one or multiple layers of biocompatible polyelectrolytes in polymer (polyvinyl pyrrolidine) and amino acids. order to stabilize their configuration. The formulation is The first powdered formulation product, Ultrasome™ based on an unconventional coating procedure of positive CoQ10, has been developed using emulsome technology poly-lysine (pLL) and negative poly-glutamic acid (pGA) with high bioavailability, excellent dissolution rate and polypeptides on small unilamellar liposomes which are dispersion. Efficacy and safety of Ultrasome™ CoQ10 has charged initially. Surface modification stabilizes the been proven by clinical trials in geriatric population. structure of liposomes, yielding a constant drug delivery Ultrasome™ CoQ10 can be filled in capsules, tablets and system. Oral administration and inclusion in bioactives are effervescent tablets [80]. Vyas et al. (2006) reported a slow the major areas of application [90]. Jain et al. prepared drug release profile (12 to 15% after 24h) and better uptake polyelectrolyte stabilized multilayered liposomes for oral of the cationic emulsome formulations of antiviral drug by delivery of paclitaxel and found that the developed the liver cells in rats [81]. Govender et al. (2008) anticipated formulation strategy can be exploited to improve the oral cationic emulsome based system which gives excellent delivery of difficult to deliver drugs [91]. potential in intracellular hepatic targeting [82]. Self-Emulsifying Systems An in vivo study reported higher concentrations of Amphotericin B in lung by surface modified liposomes and These are based on the principle that when a lipid and emulsomes as compared to those of plain counterparts by surfactant are taken in appropriate amount and when these coating amphotericin B containing aerosolized liposomes systems come in contact with the motility of the gastric and emulsomes along with alveolar macrophage specific mucosa, the agitation enables self-emulsification, forming ligands (O-palmitoylmannan, OPM) and monoclonal oil-in-water emulsion. Such systems have found favor antibody EBA-2 [83]. because they increase both the solubility and bioavailability of poorly soluble drugs [92]. These are the mixtures of oils Paliwal et al. (2009) prepared engineered carrier and surfactants, preferably isotropic, and sometimes containing emulsomes which mimicked chylomicrons for targeting co-solvents, which get emulsified to produce fine oil-in- lymph through oral delivery of methotrexate and concluded water emulsions upon gentle agitation. These usually produce that its relative bioavailability was increased nearly 5.7 times emulsions with droplet size between 100-300 nm [93]. Self- with optimized emulsome formulation compared to plain emulsifying systems are accepted as superior, when methotrexate solution with higher uptake and prolonged compared with the lipid solutions, due to the presence of residence time of methotrexate molecules in lymphatics. surfactants in the formulations, giving a more uniform and Therefore emulsome can be used as lymphotropic carrier for reproducible bioavailability [94]. delivering of bioactive(s) through oral route and also for bioavailability enhancement [84]. Escheriosomes Nanosomes These are vesicular systems which are able to fuse with cells of the plasma membrane because they are made up of Very small single bilayer nanosomes are uniform lipids extracted from the bacterium, escherichia coli. liposomes of phospholipid which are manufactured by Internalization of contents of escheriosome is possible into utilizing supercritical fluid technologies and high pressure the cytosol which makes them useful for cellular targeting. homogenization. They are nontoxic, non-antigenic and Escheriosomes are helpful in controlling intracellular biodegradable by nature due to the molecular character of pathogens by expression of particular enzymes [95, 96]. mammalian cell membranes [85]. These nanosomes are Escheriosome-based delivery helps in generating protective 40 Current Drug Therapy, 2014, Vol. 9, No. 1 Gupta et al. immunity against C. albicans infection, induces protective bilayer. These are prepared by modified reverse phase immune responses against experimental murine brucellosis evaporation technique. The use of different forms of human and for developing vaccine against leishmaniasis as well as red blood cells as oral carrier systems for human insulin has other intracellular infections [97]. been exploited as erythrosomes [105]. Bilosomes Enzymosomes Bilosomes are lipid-based vesicle systems resembling These are activated enzymes containing long circulating niosomes and consist of non-ionic amphiphiles forming a liposome for targeted drug delivery. CD39 enzyme closed bilayer structure and incorporating bile salts. Bile containing enzymosomes inhibit the platelet activation salts in niosomes stabilize the membrane in opposition to proved by in vitro and in vivo activity [106]. Enzymosomes the damaging effects of bile acids present in gastrointestinal with surface-exposed superoxide dismutase (SOD) may tract. The bilayer lipid membrane surrounds an aqueous influence the therapeutic effect and display a better activity space in which soluble vaccine candidates may be entrapped. as compared to SOD liposomes. Earlier these bile based vesicles (bilosomes) have established Ufasomes significant induction of immune response after administration through oral route, signifying a massive potential as an Ufasome is an abbreviation for unsaturated fatty acid effective carrier system for immunization through oral route liposomes, which are generated at a specific pH. The [98]. Being resistant to bile salt disruption, bilosomes formation of ufasomes is supposed to occur due to may show intrinsic adjuvant property. Earlier studies using associative interaction in mixtures of fully ionized and bilosomes and entrapped viral antigens have shown that unionized fatty acids at a pH > 7.0 [107]. Murakami et al. the bilosomes could be used to induce both the systemic and investigated the effect of oleic acid vesicles (ufasomes) on to mucosal immune responses, characterized by IgG and IgA the intestinal absorption of entrapped carboxyfluorescein antibodies respectively [99]. Mann et al. prepared bilosomes (CF) by an in-situ closed-loop method in rats. Entrapment of entrapping tetanus toxoid which was delivered orally after CF in ufasomes improved its absorption. The absorption of which significant systemic and mucosal immunity was CF was promoted much more effectively from the large induced [100]. intestine than from the small intestine. These studies suggest that ufasomes have potential as carriers for the oral Pro-Liposomes administration of poorly absorbable drugs [108]. Pro-liposomes (PLs) are unconventional forms of the Chitosomes conventional liposomal formulation which are composed of water soluble carriers, phospholipids and drugs dissolved in Basically chitosomes are liposomes coated by a organic solvent. Lipid and drug, both are coated onto a polyelectrolyte complex between chitosan (CH) and xanthan soluble carrier to form free-flowing granular material [101]. gum (XG), as a potential delivery system for oral They demonstrate controlled release, better stability, ease of administration of the protein [109]. handling and increased solubility [102]. These are modified liposomes which have the added advantage of extended shelf Cubosomes life over conventional liposomes because they are made into Cubosomes are bi-continuous cubic phases which consist a dried powder and stored. This powder is hydrated to form a of two separate, continuous, but non-intersecting hydrophilic multilamellar liposomal suspension. It is based upon the regions divided by a lipid layer that is contorted into a intrinsic property of hydrated membrane lipids in-order to periodic minimal surface with zero average curvature [110]. form vesicles on contact with water. Being available in dry Dispersed particles of bi-continuous cubic liquid crystalline powder form, they are easy to distribute, transfer, measure phase, cubosomes, are self-assembled nanostructured particles and store, making it a versatile system [103]. Some of the that can be formed in aqueous lipid and surfactant systems commonly used methods employed in the preparation of PLs [111]. The cubosomes are prepared by fragmentation techniques include film deposition on carrier method, spray drying using high-energy devices [112-114], precipitation techniques method and fluidized bed method. The delivery of liposomes [111] and dialysis of a mixed micellar solution [115]. through oral route may be improved by increasing the ability Typically, colloidal dispersions of liquid crystal are composed of liposomes to retain their veracity at the site of absorption of lipid e.g. monolinolein [116] and glycolipids [117], and can be achieved by developing them as proliposomes. amphiphiles such as poloxmer 407, phytantriol [118], alkyl Several studies have been reported which proved the glycerates and Myverol 18-99K [119]. utility of oral proliposomes in improving the solubility and bioavailability for insoluble/poorly soluble drugs. Salmon Barauskas and Landh patented the preparation of calcitonin proliposomes were also prepared and evaluated colloidal dispersions of nonlamellar lyotropic crystalline for its oral delivery. Xiao et al. prepared proliposomal phases and have termed the particles “cubosomes”. Cubosomes formulations of silymarin for administration through oral offer a largesurface area, low viscosity and can exist at route and they reported it to be stable and capable of almost any dilution level. Because of amphiphilic nature, enhancing the gastrointestinal absorption of silymarin [104]. these can be administered by different routes such as oral, parenteral, or percutaneous [117]. Erythrosomes Drugs showing limited properties of solubility and Erythrosomes are the spherically engineered vesicular permeability are difficult to incorporate in a delivery system systems in which chemically cross-linked human erythrocyte intended to be used orally. The unique liquid crystalline cytoskeleton is used as a support which is coated with a lipid structure of cubosomes may be developed to overcome the Lipid Nanoformulations for Oral Delivery of Bioactives: An Overview Current Drug Therapy, 2014, Vol. 9, No. 1 41

Table 1. List of various oral lipid based carriers and their applications in oral drug delivery.

S.No. Type OF Oral Lipid Based Drug Targeted Purpose Reference Formulations

Liposome Pluronic F127 Improvement of intestinal mucus-penetrating ability and enhanced [141] cellular uptake

Ethosome Curcumin Enhancement oral bioavailability [34] Phytosome Green tea extract Treatment of obesity [41] Pharmacosome Ketoprofen To increase oral bioavailability and minimize the gastrointestinal toxicity [142] Vesosome - Localized drug delivery [97] Archaesome Antigens Oral vaccine delivery [143] Emulsome Methotrexate Bioavailability enhancement [84] Nanosome - Improved anticancer efficacy and reduced toxicity [86] Layerosome Paclitaxel Improved oral delivery [91] Erythrosome Insulin Oral insulin delivery [105] Ufasome Carboxyfluorescein Improvement of intestinal absorption [108] Chitosome C-phycocyanin Oral delivery [109] Sphingosome - Targeting to tumor tissue [139] Cubosome Amphotericin B Treatment of fungal infections [144] Hexosome Progesterone Oromucosal delivery of Progesterone [145] Dendrosome Curcumin Treatment of Colon cancer [146] Colloidosome Insulin Maintenance of blood glucose level [147] Nanoemulsion Simvastatin Improvement of oral bioavailability [148] Solid lipid nanoparticles Insulin Oral delivery of insulin [149] Nanostructured lipid carrier Miconazole Local delivery of miconazole to oral muosa [150] Hybrid nanoparticles Amphotericin B Improvement of oral bioavailability [151]

Self-emulsifying Amphotericin B Treatment of fungal infections [152] formulations

Lipid drug conjugate Methotrexate Cancer treatment [153] Proliposome Exemestane Enhancement of oral bioavailability [154] Escheriosome C. albicans Protective immunity [155] Bilosome Tetanus toxoid Systemic and mucosal immunity [100] Aquasome Serratiopeptidase Oral delivery [156] Enzymosome Enzymes Target drugs to tumor cell [157]

above issues. It protects the drug, when exposed to harsh been established that hexosomes possess a “spinning-top- environmental conditions or enzymes in the gastrointestinal like” structure, which is to be expected to influence their tract [120]. interactions with surfaces [121, 122]. Hexosomes have been prepared by using fatty acid based and glycerate-based Hexosomes surfactants which swell to a finite degree with water [123]. Oleylglycerate, phytanylglycerate [124, 125] and tricaprylin Hexosomes are solid liquid crystalline structures which [126] have also been used. The various factors that affect the are formed by the swelling of hexagonal phases of certain formation and properties of hexasomes have been reported polar lipids when exposed to aqueous environment. By using by Amar-Yuli et al. [127]. Hydration rate and concentration cryo-field emission scanning electron microscopy, it has 42 Current Drug Therapy, 2014, Vol. 9, No. 1 Gupta et al. of polymer are the controlling factors for the symmetry, size mainly composed of natural or synthetic sphingolipids and stability of hexasomal particles. Sphingosomes offer numerous advantages over conventional vesicular systems (liposomes, niosomes) such as increased Dendrosomes stability, increased circulation time and high tumor loading Dendrosomes are neutral, biodegradable, self-assembled, efficacy in case of cancer therapy. A variety of sphingosomes hyper branched, spherical supramolecular entities with a size are available in varying sizes, composition and types [139]. ranging from 15 to 100 nm, and where the dendrimer nucleic Lipid excipients can play an active role in affecting P- acid complex is encapsulated within a lipophilic shell [128]. Glycoprotein(Pgp) mediated transport, not only by altering These are effective means of gene, DNA, siRNA delivery the membrane fluidity or ATPase activity and also by down into various kinds of cells such as cancer cells, hepatitis as regulating P-glycoprotein expression. If lipid excipients well as animal models. They posses insignificant hemolytic indeed influence transporter expression, this needs to be toxicity and higher transfection efficiency, and they are recognized by pharmaceutical and formulation scientists as better tolerated in-vivo than are dendrimers [129]. well as regulatory agencies [140]. Various types of oral lipid Colloidosomes based carrier systems and their applications in oral drug delivery as well as for targeting to various tissues have been Colloidal particles of different sizes and shapes can get recorded in Table 1. arranged on suspended particles or emulsion droplets, forming hollow-porous microcapsules called colloidosomes CONCLUSION whose permeability and elasticity can be controlled precisely Liposomes, which are bi-layered self-assembled [130]. Colloidosomes have huge potential applications in structures, are the most widely studied vesicular drug controlled release of drugs, proteins, vitamins, cosmetics and carriers in medicines since 1960s. The problems involved in food supplements [131]. developing good drug carriers have been gradually resolved Aquasomes with the advent of improved liposomes and modified lipid based vesicular carriers. The incessant progression in the Aquasomes are three-layered self-assembled nano- lipid based vesicular carriers and non- vesicular carriers play particulate carriers, comprised of a solid phase ceramic an important role in controlled delivery of various drugs.The diamond, tin oxide and calcium-phosphate dihydrate particles scope for research in the field of oral delivery of lipids is core coated with poly hydroxyl oligomeric film to which unlimited, especially when we consider the role of receptor biochemically active molecules get adsorbed with or without sites, lipidic nanoparticles and vesicular system. The modification [132]. Aquasomes are self-assembled through marketed formulations as well as patents in this field bear non-covalent bonds, ionic bonds and Vander waals forces, testimony to the fact that this approach has potential. This and were first developed by NirKossovosky in 1996 [133]. provides the formulation scientists with enough ammunition These are almost exclusively prepared by the coating of the to deliver bioactives orally in a safe and effective manner. preformed core by polyhydroxy oligomer followed by loading of the drug by co-polymerization, diffusion or CONFLICT OF INTEREST adsorption to carbohydrate surface of preformed nanoparticles. The authors confirm that this article content has no The carbohydrate coatings function as dehydro-protectant conflict of interest. and stabilizes any consequently non-covalently bound immobilized members, of biochemically reactive surface ACKNOWLEDGEMENTS members such as pharmaceuticals [134]. Declared none. The commonly used carbohydrate coating materials are REFERENCES trehalose, cellobiose, citrate, pyridoxal-5-phosphate and sucrose that exhibit dehydro-protectant activity. Aquasomes [1] Anderson BD, Rane SS. 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Received: March 11, 2014 Revised: May 05, 2014 Accepted: May 20, 2014