Micro Emulsion

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Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257
Microemulsions: A Novel Approach to Enhanced Drug Delivery

Sushama Talegaonkar*, Adnan Azeem, Farhan J. Ahmad, Roop K. Khar, Shadab A. Pathan and Zeenat I. Khan
Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India
Received: January 26, 2008; Accepted: May 15, 2008; Revised: June 1, 2008
Abstract: Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20-200 nm. They can be classified as oil-in-water (o/w), water-in-oil (w/o) or bicontinuous systems depending on their structure and are characterized by ultra low interfacial tension between oil and water phases. These versatile systems are currently of great technological and scientific interest to the researchers because of their potential to incorporate a wide range of drug molecules (hydrophilic and hydrophobic) due to the presence of both lipophilic and hydrophilic domains. These adaptable delivery systems provide protection against oxidation, enzymatic hydrolysis and improve the solubilization of lipophilic drugs and hence enhance their bioavailability. In addition to oral and intravenous delivery, they are amenable for sustained and targeted delivery through ophthalmic, dental, pulmonary, vaginal and topical routes. Microemulsions are experiencing a very active development as reflected by the numerous publications and patents being granted on these systems. They have been used to improve the oral bioavailability of various poorly soluble drugs including cyclosporine and paclitaxel as professed by Hauer et al., US patent 7235248, and Gao et al., US patent 7115565, respectively. Furthermore, they can be employed for challenging tasks such as carrying chemotherapeutic agents to neoplastic cells and oral delivery of insulin as diligently described by Maranhao, US patent 5578583 and Burnside et al., US patent 5824638 respectively. The recent commercial success of Sandimmune Neoral (Cyclosporine A), Fortovase (Saquinavir), Norvir (Ritonavir), etc. also reflects the tremendous potential of these newer drug therapeutic systems. A critical evaluation of recent patents claiming different approaches to improve the drug delivery is the focus of the current review.
Keywords: Microemulsion, self microemulsifying, microemulsion preconcentrate, thermodynamically stable, poorly soluble drugs, bioavailability, sustained and targeted drug delivery. 1. INTRODUCTION Recent progress in combinatorial chemistry has led to the generation of a large number of new compounds. Today, a large percent of these new chemical entities (NCEs) in addition to many existing drugs often show poor solubilization behaviour which lead to poor oral bioavailability with wide intra- and inter- subject variation and present formulators with considerable technical challenges. The selection of an appropriate dosage form is critical because a dosage form with poor drug delivery can make a useful drug worthless. Bioavailability has important clinical implications as both pharmacologic and toxic effects are proportional to both dose and bioavailability [1]. Many approaches have been meticulously explored to improve the oral bioavailability of such drugs including particle size reduction (micronization or nanosizing), complexation with cyclodextrins, salt formation, solubilization based on cosolvents, surfactants, etc. Modification of the physicochemical properties, such as by salt formation and particle size reduction of the drug may improve the dissolution rate of the drug but these methods are not always practical, for example, salt formation of neutral compounds is not feasible. Moreover, the salts of weak acid and weak base may convert back to their original acid or base forms and lead to aggregation in the gastrointestinal tract [2]. Particle size reduction may lead to
*Address correspondence to this author at the Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi -110062, India; Tel: +91-11- 32917377; Fax: +91-11-26059663; E-mail: stalegaonkar@jamiahamdard.ac.in 1872-2113/08 $100.00+.00
build up of static charges, present handling difficulties and is not desirable where poor wettability are experienced for very fine powders. To overcome these limitations, various other formulation strategies have been attempted such as use of cyclodextrins, nanoparticles, solid dispersions and permeation enhancers [1, 3]. Indeed, in some selected cases, these approaches have been successful. Some of the approaches have been highlighted in Fig. (1). Of late lipid-based formulations have attracted great deal of attention to improve the oral bioavailability of poorly water soluble drugs. In fact, the most favoured approach is to incorporate lipophilic drugs into inert lipid vehicles such as oils, surfactant dispersions, microemulsions, self-emulsifying formulations, self microemulsifying formulations, and liposomes [4-14]. This could lead to increased solubilization with concomitant modification of their pharmacokinetic profiles, leading to increase in therapeutic efficacy. Microemulsions have been widely studied to enhance the bioavailability of the poorly soluble drugs. They offer a cost effective approach in such cases. Microemulsions have very low surface tension and small droplet size which results in high absorption and permeation. Interest in these versatile carriers is increasing and their applications have been diversified to various administration routes in addition to the conventional oral route. This can be attributed to their unique solubilization properties and thermodynamic stability which has drawn attention for their use as novel vehicles for drug delivery. The results obtained have been indeed very promising. In recent past, microemulsion formulation of a
2008 Bentham Science Publishers Ltd.
Microemulsions in Drug Delivery
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Fig. (1). Some of the formulation approaches to improve the oral bioavailability of poorly water soluble drugs.
poorly soluble immunosuppressant was marketed as a soft capsule which contains a mixture of drug dissolved in oil and surfactant [15-17]. It converts into an oil-in-water (o/w) microemulsion in situ in an aqueous environment in the stomach and the small intestine. Microemulsion formulation made the bioavailability and plasma concentration profiles of the drug more reproducible which is clinically important in the case of drugs showing serious adverse effects. This is a significant step forward in the delivery of poorly soluble drugs. Microemulsion systems are also now being increasingly investigated for transdermal [18-22], ocular [23], nasal [24, 25], pulmonary [26], vaginal [27, 28], rectal [29, 30] and intravenous drug delivery [31]. This review focuses on recent developments in the field of microemulsion technology with respect to drug delivery. The article summarizes the recently introduced patents on microemulsion systems and explores their potential in the delivery of poorly soluble drug compounds in particular in addition to their novel applications. 2. MICROEMULSIONS In 1959, Schulman et al. visualized the existence of small emulsion-like structures by electron microscopy and subsequently coined the term microemulsions [32]. Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20-200 nm. These homogeneous systems, which can be prepared over a wide range of surfactant concentration and oil to water ratio, are all fluids of low viscosity. Microemulsions as drug delivery tool show favourable properties like thermodynamic stability (long shelf-life), easy formation (zero interfacial tension and almost spontaneous formation), optical isotropy, ability to be sterilized by filtration, high surface area (high solubilization capacity) and very small droplet size. The small droplets also provide better adherence to membranes and transport drug molecules in a controlled fashion. Microemulsions are easy to administer to children and to people who have difficulty swallowing solid oral dosage forms. The key differences
between ordinary emulsions (macro emulsions) and microemulsions are shown in Table 1. A self microemulsifying drug delivery system (SMEDDS) is an anhydrous system of microemulsions. It has also been referred to as microemulsion preconcentrate by some researchers. It is composed of oil, surfactant and cosurfactant and has the ability to form o/w microemulsion when dispersed in aqueous phase under gentle agitation. The agitation required for the self-emulsification comes from stomach and intestinal motility [33-35].The nanosized droplets have very high surface to volume ratios which are able to efficiently solubilize the drug. The drug is released in a more reproducible manner which will become less dependent on the GI physiology and the fed/fasted state of the patient. Since the drug delivery system should be mild and biocompatible, the choice of excipients is, however, limited. Also a large amount of surfactant is required for microemulsion formation which is undesirable. Therefore, proper selection of the components and their use concentration is imperative for a wider acceptability. The field of existence of microemulsion is generally narrow and their temperature stability, particularly of nonionic surfactant containing microemulsions, can be limited. 2.1. Structure Microemulsions are dynamic systems in which the interface is continuously and spontaneously fluctuating [36]. Structurally, they are divided into oil-in-water (o/w), waterin-oil (w/o) and bicontinuous microemulsions. In w/o microemulsion, water droplets are dispersed in the continuous oil phase while o/w microemulsion is formed when oil droplets are dispersed in the continuous aqueous phase. In systems where the amounts of water and oil are similar, a bicontinuous microemulsion may result. In all three types of microemulsions, the interface is stabilized by an appropriate combination of surfactants and/or co-surfactants. The mixture of oil, water and surfactants is able to form a wide variety of structures and phases depending upon the proportions of the components. The flexibility of the surfactant film is an important factor in this regard. A flexible surfactant film will enable the existence of several different structures like droplet like shapes, aggregates and
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Table 1.
S. No 1 2 3 4 5 6
Comparison of Microemulsion with Conventional Emulsion

Property Appearance Optical Isotropy Interfacial tension Microstructure Droplet size Stability Microemulsion Transparent (or translucent) Isotropic Ultra low Dynamic (interface is continuously and spontaneously fluctuating) 20-200 nm Thermodynamically stable, long shelf-life Emulsion Cloudy Anisotropic High Static > 500 nm Thermodynamically unstable (kinetically stable), will eventually phase separate Biphasic Require a large input of energy, higher cost Higher viscosity
7. 8 9
Phases Preparation Viscosity
Monophasic Facile preparation, relatively lower cost for commercial production Low viscosity with Newtonian behaviour
bicontinuous structures, and therefore broaden the range of microemulsion existence. A very rigid surfactant film will not enable existence of bicontinuous structures which will impede the range of existence. Besides microemulsions, structural examinations can reveal the existence of regular emulsions, anisotropic crystalline hexagonal or cubic phases, and lamellar structures depending on the ratio of the components. The internal structure of a microemulsion vehicle is very important for the diffusivity of the phases, and thereby also for the diffusion of a drug in the respective phases. Researchers have been trying zealously to understand the complicated phase behaviour and the various microstructures encountered in the microemulsion systems [37]. 2.2. Components of Microemulsion Formulations A large number of oils and surfactants are available which can be used as components of microemulsion systems but their toxicity, irritation potential and unclear mechanism of action limit their use. One must choose materials that are biocompatible, non-toxic, clinically acceptable, and use emulsifiers in an appropriate concentration range that will result in mild and non-aggressive microemulsions. The emphasis is, therefore, on the use of generally regarded as safe (GRAS) excipients. Oil Phase The oil component influences curvature by its ability to penetrate and hence swell the tail group region of the surfactant monolayer. Short chain oils penetrate the tail group region to a greater extent than long chain alkanes, and hence swell this region to a greater extent, resulting in increased negative curvature (and reduced effective HLB) [38]. Saturated (for example, lauric, myristic and capric acid) and unsaturated fatty acids (for example, oleic acid, linoleic acid and linolenic acid) have penetration enhancing property of their own and they have been studied since a long time. Fatty acid esters such as ethyl or methyl esters of lauric, myristic and oleic acid have also been employed as the oil phase.
Lipophilic drugs are preferably solubilized in o/w microemulsions. The main criterion for selecting the oil phase is that the drug should have high solubility in it. This will minimize the volume of the formulation to deliver the therapeutic dose of the drug in an encapsulated form. Surfactants The surfactant chosen must be able to lower the interfacial tension to a very small value which facilitates dispersion process during the preparation of the microemulsion and provide a flexible film that can readily deform around the droplets and be of the appropriate lipophilic character to provide the correct curvature at the interfacial region. It is generally accepted that low HLB surfactants are favoured for the formulation of w/o microemulsion, whereas surfactants with high HLB (>12) are preferred for the formation of o/w microemulsion. Surfactants having HLB greater than 20 often require the presence of cosurfactants to reduce their effective HLB to a value within the range required for microemulsion formation. Cosurfactants In most cases, single-chain surfactants alone are unable to reduce the o/w interfacial tension sufficiently to enable a microemulsion to form [39-42]. The presence of cosurfactants allows the interfacial film sufficient flexibility to take up different curvatures required to form microemulsion over a wide range of composition [38, 43-45]. If a single surfactant film is desired, the lipophilic chains of the surfactant should be sufficiently short, or contain fluidising groups (e.g. unsaturated bonds). Short to medium chain length alcohols (C3-C8) are commonly added as cosurfactants which further reduce the interfacial tension and increase the fluidity of the interface. 2.3. Method of Preparation 2.3.1. Phase Titration Method Microemulsions are prepared by the spontaneous emulsification method (phase titration method) and can be depicted with the help of phase diagrams. Construction of
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phase diagram is a useful approach to study the complex series of interactions that can occur when different components are mixed. Microemulsions are formed along with various association structures (including emulsion, micelles, lamellar, hexagonal, cubic, and various gels and oily dispersion) depending on the chemical composition and concentration of each component. The understanding of their phase equilibria and demarcation of the phase boundaries are essential aspects of the study. As quaternary phase diagram (four component system) is time consuming and difficult to interpret, pseudo ternaryphase diagram is often constructed to find the different zones including microemulsion zone, in which each corner of the diagram represents 100% of the particular component Fig. (2). The region can be separated into w/o or o/w microemulsion by simply considering the composition that is whether it is oil rich or water rich. Observations should be made carefully so that the metastable systems are not included. The methodology has been comprehensively discussed by Shafiq-un-Nabi et al. [46].
curvature of the surfactant from initially stabilizing a w/o microemulsion to an o/w microemulsion at the inversion locus. Short-chain surfactants form flexible monolayers at the o/w interface resulting in a bicontinuous microemulsion at the inversion point. 2.4. Characterisation The characterization of these systems is highly challenging due to their small droplet size with fluctuating boundaries and complex structure. Basic components in a physicochemical characterization of microemulsion systems are: 1. 2. Phase stability and phase behavior, Microstructure, dimension (size and size distribution), shape and surface features (specific area, charge, and distribution), Local molecular dynamics. arrangements, interactions and
3.
Fig. (2). Pseudoternary phase diagram of oil, water and surfactant showing microemulsion region.
Among these properties, particle size, interactions, and dynamics are of fundamental importance since they control many of the general properties of microemulsions. In particular, the size distributions of microemulsions give essential information for a reasonable understanding of the mechanism governing both the stability and penetration into the membrane [47, 48]. Many technologies like dynamic light scattering (DLS) [4, 49], small angle neutron scattering (SANS) [50-52] and small angle X-ray scattering (SAXS) [53-58] as well as cryo transmission electron microscopy [59-62] and pulsed field gradient spin echo (self-diffusion) NMR [63-67] have been in growing use in particle size characterization. Other methods, e.g. electrokinetic chromatography, conductance, viscosity, electrical birefringence, infrared spectroscopy and calorimetry are also employed for investigating the internal physicochemical states of microemulsions [40, 56, 68-71]. Viscosity measurement can indicate the presence of rodlike or worm-like reverse micelles while conductivity measurement provides a means of determining whether a microemulsion is oil-continuous or water-continuous as well provide a means of monitoring phase inversion phenomena [43]. Dielectric measurements are a powerful means of probing both the structural and dynamic features of microemulsion systems. Pulsed field gradient NMR is also used extensively to measure self-diffusion coefficients of the various components and yields information on the mobility and microenvironment. 3. MICROEMULSIONS IN DRUG DELIVERY During the last two decades, microemulsions have been extensively researched because of their tremendous potential in many applications. The role of microemulsions in drug delivery and the patents granted shall be discussed comprehensively herein . 3.1. Oral Delivery The development of the effective oral delivery systems has always been the main goal because drug efficacy can be severely limited by instability or poor solubility in the gastrointestinal fluid. Biopharmaceutical Classification
2.3.2. Phase Inversion Method Phase inversion of microemulsions occurs upon addition of excess of the dispersed phase or in response to temperature. During phase inversion drastic physical changes occur including changes in particle size that can affect drug release both in vivo and in vitro. These methods make use of changing the spontaneous curvature of the surfactant. For non-ionic surfactants, this can be achieved by changing the temperature of the system, forcing a transition from an o/w microemulsion at low temperatures to a w/o microemulsion at higher temperatures (transitional phase inversion). During cooling, the system crosses a point of zero spontaneous curvature and minimal surface tension, promoting the formation of finely dispersed oil droplets. This method is referred to as phase inversion temperature (PIT) method. Instead of the temperature, other parameters such as salt concentration or pH value may be considered as well instead of the temperature alone. Additionally, a transition in the spontaneous radius of curvature can be obtained by changing the water volume fraction. By successively adding water into oil, initially water droplets are formed in a continuous oil phase. Increasing the water volume fraction changes the spontaneous
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System (BCS) is a useful guidance by US FDA and it takes into account contributions of three major factors, dissolution, solubility, and intestinal permeability, which affect oral drug absorption. According to the BCS, drug substances are classified as follows: Class I - High Permeability, High Solubility Class II - High Permeability, Low Solubility Class III - Low Permeability, High Solubility Class IV - Low Permeability, Low Solubility Knowledge of BCS help the formulation scientists to develop a dosage form based on mechanistic, rather than empirical approaches. Drug substances are considered highly soluble when the largest dose of a compound is soluble in <250 mL of water over a range of pH from 1.0 to 7.5 and highly permeable when they show >90 percent absorption of the administered dose [1, 72]. In contrast, compounds with solubility below 0.1mg/mL provide significant dissolution related problems, and often, even compounds with solubility below 10mg/mL present difficulties related to solubilization during formulation. A major technological hurdle for routine clinical use of many drugs is their very poor solubility in water. Microemulsions have the potential to enhance the solubilization of the poorly soluble drugs and overcome the dissolution related bioavailability problems. This is particularly important for the BCS class II or class IV drugs. The successful formulation of such drugs is highly dependent on the performance of the formulated product. Microemulsions act as super solvent of these drugs and can be optimized to ensure consistent bioavailability. In addition, they can be used for the delivery of hydrophilic drugs including macromolecules such as proteins and peptides. This is due to the existence of polar, nonpolar and interfacial domains which allow encapsulation of drugs with varying solubility. Moreover, these systems have been reported to protect the incorporated drugs against oxidation, enzymatic degradation [73] and enhance the membrane permeability [74]. Presently, Sandimmune Neoral (Cyclosporine A), Fortovase (Saquinavir), Norvir (Ritonavir), etc. are the commercially available SMEDDS formulations. A detailed illustration of their role in oral drug delivery is discussed in this section. 3.1.1. Bioavailability Enhancement of Poorly Water Soluble Drugs Paclitaxel, an anticancer drug, has poor aqueous solubility and therefore, formulation of paclitaxel has proven to be difficult. Gao et al. disclosed self emulsifying compositions that generated a supersaturated paclitaxel microemulsion upon contact with water in vivo that permitted its rapid and efficient absorption resulting in improved oral bioavailability [75]. The composition comprised of a solvent, a surfactant, a substituted cellulosic polymer (e.g. hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, etc.), and optionally a Pglycoprotein inhibitor. Paclitaxel and surfactant were present in a ratio of from about 1:3 to about 1:20 by weight; and the substituted cellulosic polymer and paclitaxel were present in a ratio of from about 50:1 to about 0.1:1 by weight. The oral
administration of a commercial product, Taxol (Bristol Myers Squibb) showed approximately 10-fold lower Cmax than that obtained with their composition in rats. Farah et al. in US Patent 6054136 provided a SMEDDS capable of forming a microemulsion in situ with the physiological fluid of the stomach and intestine for the enhancement of drug bioavailability [76]. The SMEDDS consisted of an active constituent, a lipophilic phase, a surfactant and a cosurfactant. The lipophilic phase consisted of a mixture of C8-C18 polyglycolized glycerides having a HLB of less than 16. Surfactant was chosen from the group comprising saturated C8-C10 polyglycolized glycerides and oleic esters of polyglycerol also having an HLB of less than 16 (e.g. Labrasol, Labrafac CM 10) and cosurfactant was chosen from the group comprising lauric esters of propylene glycol (Lauroglycol), oleic esters of polyglycerol and ethyl diglycol (Transcutol). The surfactant/cosurfactant ratio was between 0.5 and 6. The composition being free from aqueous phase would facilitate packaging in hard gelatin capsules. The US Patent 6312704 granted to the same inventors was the extension of their earlier patent [77]. In that there was an additional claim in which it was said that lipophilic phase was obtained by esterification of polyethylene glycol and glycerol with fatty acids, or by mixing of glycerol esters and condensates of ethylene oxide with fatty acids. The surfactant was selected from the group consisting of oleic esters of polyglycerol or a product obtained by esterification of glycerol and polyethylene glycol with caprylic acid and capric acid, or by mixing of glycerol esters and condensates of ethylene oxide with caprylic acid and capric acid. The use of rapamycin (macrolide antibiotic) and its structurally similar analogs are limited by their very low solubility, low and variable bioavailability and their high toxicity. They have potent immunosuppressive activity and also antitumor and antifungal activity. Fricker et al. taught a microemulsion preconcentrate carrier medium for their effective oral delivery [78]. The carrier medium comprised a reaction product of a castor oil and ethylene oxide; a transesterification product of a vegetable oil and glycerol comprising predominantly linoleic acid or oleic acid, mono-, di-, and triglycerides or a polyoxyalkylated vegetable oil; 1,2 -propylene glycol; and ethanol. When administered orally high and consistent absorption was obtained. Therefore, the macrolide might be administered in lower doses, which might alleviate toxicity problems. Earlier they had described a microemulsion preconcentrate for their delivery comprising hydrophilic component (Transcutol, Glycofurol, 1,2-propylene glycol, or their mixtures), a lipophilic component selected from the group consisting of fatty acid triglycerides (Miglyol, Captex, Capmul, etc.), mixed mono-, di-,and tri-glycerides and transesterified ethoxylated vegetable oils (e.g. Maisine), and a surfactant which was selected from the group consisting of polyethyleneglycol, natural or hydrogenated castor oils (Cremophor EL, Cremophor RH40), polyethylene-sorbitan fatty acid esters (Tweens), polyoxyethylene fatty acid esters (Myrj), polyoxyethylene-polyoxypropylene co-polymers, and block co-polymers (Pluronic, Polaxamers) [79]. The composition on dilution with water gave a microemulsion having an average particle size of <150 nm.
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Liang et al. disclosed self-emulsifying formulations of fenofibrate or fenofibrate derivatives having an improved oral bioavailability and/or reduced food effect when compared to commercial available formulations such as Lipanthyl (Groupe Fournier) or TriCor. (Abbott Laboratories) [80].The particle size of the active agent was not critical to the bioavailability of the product. Fenofibrate or fenofibrate derivative was dissolved in a solubilizer that allowed the complete dissolution of the fenofibrate or a fenofibrate derivative and prevented or minimized the crystallization of fibrate in the formulation. With the complete dissolution of the fibrate, the fibrate solution allowed for an increase in absorption of the fibrate by the patient. Some of the earlier strategies for increasing the bioavailabilty included the use of micronized fenofibrate [81-84], use of diethylene glycol monoethyl ether as solubilizer [85], etc. Bioavailability for orally administered conventional crystalline or amorphous forms of cholesterol ester transfer protein (CETP) inhibitors is quite low, often having absolute bioavailabilities of less than 1%. Gumkowski et al. provided self-emulsifying or self-microemulsifying compositions for the improved solubility and bioavailability of CETP inhibitors [86]. The formulation had a CETP inhibitor, a cosolvent, a surfactant having an HLB of 1 to 8, a surfactant having an HLB of over 8 to 20, and optionally a digestible oil. Lambert et al. provided a composition which could be a emulsion or a microemulsion having oil and a water phase for improving the solubility of poorly soluble drugs [87]. Chemotherapeutic agent could be a taxoid, a taxane, or a taxine, preferably paclitaxel. Alpha-tocopherol or a tocopherol polyethylene glycol succinate was also incorporated in the oil phase. The resulting formulation was inexpensive, sterilizable by either heat or filtration, stable for at least a year and accommodated a wide variety of water insoluble and poorly soluble drugs and was ethanol-free. Non-aqueous solvents and solubilizers such as alcohol used in pharmaceutical formulations may extract toxic substances, for example plasticizers, from their containers. This may cause adverse reactions such as respiratory distress. This problem could be circumvented by their invention. The US Patent 6660286 described a similar composition which in addition claimed a composition consisting of paclitaxel, one or more tocopherols or their derivatives, a tocopherol polyethylene glycol derivative, polyethylene glycol, a polyoxypropylenepolyoxyethylene glycol nonionic block polymer, and an aqueous phase [88]. Benameur et al. have found that the incorporation of an active agent, particularly statins, into a self-microemulsifying system made it possible to reduce the first intestinal passage effect, and thus improve the systemic bioavailability of the active molecule [89]. Earlier SMEDDS had been reported to improve the solubility of the waterinsoluble active principles but there was no knowledge on the action of SMEDDS on intestinal metabolism. The inventors had found surprisingly that the incorporation of an active principle (statins) with a strong first intestinal passage effect into a self-microemulsifying system made it possible to reduce the first intestinal passage effect, and thus
improved the systemic bioavailability of the active molecule. The self micro-emulsfying carrier included a lipophilic phase, which was a mixture of glycerol mono-, di- and triesters and of PEG mono- and diesters with at least one fatty acid chosen from the group comprising C8 - C18 fatty acids (LabrafilM1944CS), a surfactant phase which is a mixture of glycerol mono-, di- and triesters and of PEG mono- and diesters with caprylic acid (C8) and capric acid (C10) (Capryol 90), a co-surfactant phase which was an ester of a polyvalent alcohol with at least one fatty acid chosen from the group comprising caprylic esters of propylene glycol, lauric esters of propylene glycol and oleic esters of polyglycerol. The ratio of surfactant/cosurfactant varied between 0.2 and 6. The object of the invention of von Corswant was to provide a vehicle which increased the solubility of compounds having a low solubility in water and at the same time being non-toxic [90]. In that direction he presented a non-toxic o/w or bicontinous microemulsion which was comprised of a polar phase comprising water and a component for adjusting the polarity of the polar phase, a surfactant film modifier which is a monohydric alcohol with 2-3 carbon atoms (e.g. ethanol), a non-polar phase comprising oil, and a mixture of a hydrophilic surfactant and a hydrophobic surfactant which was selected from the group consisting of lecithin, sphingolipids and galacto lipids. The inventors had found that by using at least two types of modifiers for adjusting the polarity it was possible to minimize the amount of the surfactant and thus, also the toxicity was minimized. Chen et al. described a microemulsion of pyranone protease inhibitor compounds that was free of alcohol and propylene glycol comprising a pyranone protease inhibitor, surfactant, and a polyethylene glycol solvent having a mean molecular weight of greater than 300 but lower than 600, and a lipophilic component comprising medium chain mono- and di-glycerides, and optionally a basic amine [91]. The formulations of this invention provided for improved solubilization, stability and/or bioavailability of the pyranone drug and permit less arduous manufacturing processes to be undertaken in the fill process and allow the capsules to be stored at room temperature. Gao et al. provided pharmaceutical compositions in a self-emulsifying formulation which permitted a high loading of lipophilic compounds (up to about 400 mg/g) in addition to good oral bioavailability [92]. The novel composition comprised a lipophilic drug , a mixture of diglyceride and monoglyceride in a ratio of from about 9:1 to about 6:4 by weight wherein the diglyceride and monoglyceride are mono- or di- unsaturated fatty acid esters of glycerol having sixteen to twenty-two carbon chain length, solvent and surfactant. The composition might be in the form of liquid for soft elastic capsules or hard gelatin capsules for oral application and might also be in the form of a liquid solution for oral, parenteral, rectal or topical application. In their earlier patent they had mentioned the use of pyranone compound as the active agent [93]. They also provided a formulation for pyranone compounds which was based on the use of a particular amount (0.1% to about 10% by
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weight) of the basic amine along with solvents, surfactants and oil [94]. The invention of Bauer et al. included o/w microemulsion containing one polyglycerol ester as the emulsifier and lipophilic substance as the internal phase [95]. The emulsifier contained a triglycerol monofatty acid ester (e.g. triglycerol monolaurate, triglycerol monocaprylate) and the lipophilic substance was selected from the group consisting of carotenoids, vitamins A, D, E and K and their derivatives and polyunsaturated fatty acids. The emulsifiers used were non-toxic and such microemulsions could also be used in foodstuffs in addition to the pharmaceutical field. Mishra et al. described self-emulsifying microemulsion or emulsion preconcentrate formulations containing omega-3 fatty acid oil and a hydrophobic drug [96]. The drug was soluble in the omega-3 fatty acid oil and the preconcentrates were free of or contain only minor amounts of a hydrophilic solvent system. US Patent 4678808 described the use of these oils to treat disorders associated with arachidonic acid metabolites, including autoimmune syndromes, acute and chronic inflammatory diseases, atherosclerosis, etc. [97]. The omega-3 fatty acid oil and drug can exert an additive or synergistic therapeutic effect or the omega-3 fatty acid oil counteracts the negative side effects of the therapeutic agent. For example, cyclosporines are soluble in omega-3 fatty acid oil and capable of exerting an additive or synergistic therapeutic effect in various autoimmune and inflammatory diseases. In addition, the omega-3 fatty acid oil mediated the adverse side effects, such as nephrotoxicity, of a cyclosporine such as cyclosporine A by reduction of its dose. The composition could be administered in soft or hard gelatin capsule. Crison et al. taught a self-microemulsifying formulation for increasing the bioavailability of a drug which included oil/ lipid material, a surfactant, and a hydrophilic co-surfactant [98]. HLB of hydrophilic co-surfactant was greater than 8. The self-microemulsifying formulation could also include the addition of an aqueous solvent such as triacetin. They had found that a more hydrophilic co-surfactant not only increased the dissolution of poorly water-soluble drugs but, that it also increased their in vivo bioavailability. Orally administered acyclovir (in tablet, capsule or suspension form) is slowly and erratically absorbed with 1530% bioavailability. For improved patient compliance an acyclovir preparation is required which would permit lower dosing and less frequent administration. In one embodiment of their invention Burnside et al. provided a pharmaceutical preparation comprising a w/o emulsion, preferably a microemulsion, containing an oil phase (such as a long chain carboxylic acid or ester or alcohol thereof), a surfactant (such as poloxamer) and an aqueous phase containing the drug acyclovir [99]. It was found that microemulsions were ideal for oral acyclovir delivery since they contain homogeneous and uniform droplet size of approximately 2040 nm and had the ability to dissolve relatively large amounts of polar solutes in an overall oily environment. The outer oily phase of the microemulsion was able to incorporate into the intestinal cell matrix, thus creating channels (either paracellularly or transcellularly) through which the acyclovir could pass. Thus, malabsorption in the
intestine could be circumvented. Further, the work of Rudnic et al. described a pharmaceutical preparation comprising a stable, surface-active emulsion or dispersion of a pharmaceutical agent incorporated into an emulsion having a hydrophobic discontinuous phase of a long chain carboxylic acid (e.g. lauric acid, capric acid, myristic acid, behenic acid, etc.) or ester (glyceryl monostearate, glyceryl monopalmitate, etc.) or alcohol thereof dispersed in an aqueous phase or having a hydrophilic discontinuous phase dispersed in a hydrophobic phase of a long chain carboxylic acid or alcohol thereof [100]. The materials when combined in accordance with the invention to form a w/o microemulsion gave enhanced absorption capabilities. Melatonin is a hormone synthesized in the epiphysis, in the retina and, presumably in the chromaffinic cells of the intestinal tract. It has immunostimulant and immunomodulatory effects. An attempt had been made by Graziella et al. to improve the oral bioavailability of melatonin [101]. They described a microemulsion containing melatonin, Lalpha-phosphatidylcholine (emulsifier) and a solvent mixture consisting of ethanol, propylene glycol and water in which the weight ratio of L-alpha-phosphatidylcholine to melatonin was about 1:1. Eugster et al. taught in their invention a spontaneously dispersible concentrate which formed an ultramicroemulsion when diluted with water or a glucose solution [102]. The concentrate contained sterolester and/or sterolphosphor compounds, surfactant, vitamin or provitamin, free fatty acid and a carrier or diluent. They had found that the newly synthetised sterolesters and sterolphosphatides had a pronounced antitumour activity, particularly if these compounds were being incorporated into spontaneously dispersible concentrates. Ecanow proposed drug delivery systems which included one or more monomeric or polymerized surface active agents (e.g. polymerized lecithin) which allowed for rapid dissolution and smooth liberation of the incorporated drug [103]. Stable microemulsions could be produced by encasing the microemulsions in a coacervate phase matrix and/or film. Table 2 shows the utilization of the microemulsion technology to improve the solubility and bioavailability of some of the poorly water soluble drugs. 3.1.2. Controlled and Sustained Release of Drugs US Patent 7147867 disclosed a sustained-release dosage form for the delivery of a progestogenic steroid comprising of a capsule, a self-emulsifying drug formulation contained within a first portion of the capsule, an expandable layer contained within a second portion of the capsule [104]. The expandable layer was so positioned that the self-emulsifying drug formulation could be expelled from the capsule upon expansion of the expandable layer and a semipermeable membrane is formed over at least a portion of an outer surface of the capsule Fig. (3). The semipermeable membrane comprised of a thermoplastic polymer composition having a softening point of 40- 180oC. The aqueous fluid dissolved the gelatin capsule and the imbibed fluid caused the push-displacement layer to expand and push the emulsified formulation through an orifice at a controlled rate. The dosage form comprising the liquid formulation
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Table 2.
S. No 1
Bioavailability Enhancement of Some Drugs Using Microemulsion Technology

Drug Paclitaxel Category Anticancer System SMEDDS Microemulsion Ref. [75] [87] [80] [86] [89] [78] [97] [90] [100] [76] [95] [109] [91] [92] [96] [99] [102]
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Fenofibrate Cholesterol ester transfer protein (CETP) inhibitors Atorvastatin, Fluvastatin Rapamycin Cyclosporine Felodipine Nifedipine Indomethacin Ibuprofen Naproxen Tipranavir Progesterone, Testosterone Vitamins (A,D, E, K) Acyclovir Melatonin Anti HIV Hormones Nutrition supplement Antiviral Immunomodulatory Analgesic Antihypertensive Immunosuppressive Antihyperlipidimic
SMEDDS SMEDDS SMEDDS SMEDDS SMEDDS Microemulsion SMEDDS SMEDDS SMEDDS SMEDDS Microemulsion SMEDDS Microemulsion Microemulsion Microemulsion
provided various advantages such as improved solubility, improved bioavailability, sustained release and inhibition of crystal growth during storage thereby providing improved stability. Gattefosse had been assigned a patent for a composition with sustained release of active agent which was capable of forming a microemulsion with an external hydrophilic phase, for example physiological fluid or water [105]. The composition comprised of an inert polymeric matrix which couldnt be ionised at physiological pH, dispersed in the microemulsion forming system. After ingestion, polymeric matrix on contacting the physiological fluid formed a gelled polymeric matrix. The gelled barrier controlled the penetration of water from the outside inwards, making possible the gradual release of the microemulsified active principle by diffusion, in a continuous and prolonged manner. Figure (4). shows the functioning of the polymer matrix dispersed in a SMEDDS formulation, the composition obtained being in the form of gel capsule. ALZA Corporation had been assigned a patent for a sustained release self emulsifying formulation to enhance the solubility, the dissolution, and the bioavailability of the drug [106]. The formulation process involved the following steps: (a) blending an osmotic hydrogel and an osmotically effective solute, (b) blending a hydroxyalkylcellulose and water to provide a granulation solution, (c) spraying the granulation solution of step (b) onto the composition provided in step (a) to provide granules, (d) forming a
blended, liquid mixture consisting essentially of a drug, a surfactant, and a member selected from the group consisting of a mono- and di-glyceride to provide a liquid self-emulsifying drug formulation, (e) adding the drug formulation formed in step (d) to a capsule, (f) adding the sprayed composition of step (c) to the capsule, (g) coating the capsule with a semipermeable composition to provide a membrane permeable to an aqueous fluid and providing an exit in the membrane for delivering the drug formulation at a sustained-release and controlled rate over an extended period of time. 3.1.3. Manufacturing Improvements SMEDDS based formulations require filling into soft or hard gelatin capsules. Some of the problems encountered in the processing of liquid SMEDDS include leaching and leakage of the formulation, interaction with capsule shell components and handling difficulties for the manufacturers. It is therefore of interest to incorporate the self microemulsifying vehicles into a powder to produce solid dosage forms which may provide an attractive alternative to filledcapsule preparations. The proper excipients selection, however, is crucial when formulating dry adsorbed solid formulations. A comprehensive review on these systems focusing on formulation considerations, selection and function of solidifying excipients and techniques of preparation has been published recently [107].
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Fig. (3). Dosage form comprising a capsule made of two parts consisting of a body portion and a cap portion in which capsule contains a drug microemulsion formulation and an expandable composition.
Pather et al. provided a method for converting drugcontaining microemulsion or self-microemulsifying drug delivery system into a free-flowing, compressible powder by admixing drug-containing microemulsion or self-microemulsifying drug delivery system with a solid particle adsorbent such as silicon dioxide, clays, magnesium trisilicate, talc, etc. [108]. The composition could be further formulated into solid dosage forms. Advantages of this invention were numerous and helped in eliminating or reducing the problems encountered with the earlier formulations. For example, w/o microemulsion can absorb water from gelatin shells. This may change the proportions of the different phases and may cause the gelatin shell to become dry and susceptible to cracking. The gelatin may absorb water from w/o microemulsion and becomes soft. Surfactants and co-surfactants within the microemulsions can also react with the capsule shell. On the other hand, o/w microemulsions cannot be incorporated in such capsules because the water in the external phase would react with the capsule shell. Capsules containing liquids also present handling problems to the manufacturers. Capsules leakage is a common problem. Presentation of microemulsions in a solid dosage form provided a more robust, stable dosage that was convenient and easy to handle. The invention of Mulye was concerned with selfemulsifying compositions for poorly soluble drugs [109]. Their composition included a lipophilic drug in association with a carrier which was comprised of a lipophilic drug solubilizing effective amount of a propylene glycol monoester of C6-C18 fatty acid having at least 60% by weight monoester based on the total weight of the propylene glycol ester (e.g. propylene glycol monocaprylate) and a non-ionic surfactant. Due to the greater solubility of lipophilic drugs in the carrier, the capsule size was reduced, providing greater patient acceptance and compliance. Moreover, there was an excellent compatibility of the propylene glycol ester with a hard or soft shell gelatin capsule or with a non-gelatin capsule, thereby preventing brittleness and leakage of the formulation during storage. Another advantage was that the composition formed a microemulsion upon exposure to aqueous fluid in the gastrointestinal tract which would provide enhanced bioavailability. 3.1.4. Protein and Peptide Drug Delivery Numerous peptide and proteins have been identified for use as novel therapeutic agents. With increase in the understanding of their structure and mechanism, recent research has shifted to biotechnological products [110]. Changing scenario and increased market competitiveness is pressurizing companies to address significant protein delivery issues already at late discovery and early development stages. However, in spite of tremendous advances in peptide and protein development, their delivery is limited to systemic route. This is due to their low oral bioavailability which can be ascribed to their inactivation by gastrointestinal enzymes and poor permeability of the intestinal mucosa. To circumvent this, microemulsions have been developed as smart systems and patented for the oral delivery of protein and peptide drugs.
Fig. (4). Functioning of the polymer matrix dispersed in a SMEDDS formulation.
One preferred embodiment of the invention of Burnside et al. comprised of a microemulsion containing an oil phase
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(such as a long chain carboxylic acid or ester or alcohol thereof), a surface active agent (such as a poloxamer) and an aqueous phase containing the insulin [111]. They had attempted to increase the intestinal absorption of the hormone which had met with only limited success earlier. The hydrophobic material formed the continuous phase and the hydrophilic material formed the discontinuous phase in which the hydrophilic material was emulsified (w/o). A large amount of polar solutes could be dissolved in an overall oily environment by using w/o microemulsion thereby creating an oral delivery system for oral delivery of insulin. Cho et al. taught in US Patent 5656289 that oral proteinaceous compositions comprising w/o microemulsions could form chylomicra or provide chylomicra to sites of absorption in the gastrointestinal tract [29]. It is believed that when a biologically active material is administered in association with chylomicra or the constituents of chylomicra, it is targeted to the villae and microvillae of the intestinal wall, from where it is secreted into the lacteals and intestinal lymph and then drained into the thoracic duct and, ultimately, the circulating bloodstream. Therefore, proteinaceous active agents administrable only parenterally can be given by the more preferred oral or rectal route. Formulations of the invention were suitable for the oral administration of insulin in the treatment of diabetes. w/o formulation for proteinaceous compounds comprised of a hydrophilic phase dispersed in a lipophilic phase to form an emulsion/microemulsion wherein hydrophilic phase comprises water, a biologically active substance and lecithin or a lecithin precursor comprising a phospholipid, and lipophilic phase comprises oil, a phospholipid and a lipophilic surfactant [30]. Lecithin can integrate into chylomicra, particularly into their membranes and ultimately carries the protein with it into general circulation. The invention of Cho et al. provided pro-micelle compositions (microemulsion or liposome) comprising a pharmaceutically active agent encapsulated with a membrane of esterified C12 -C18 fatty acids wherein the concentration of fatty acid is less than 15 weight % [112]. In the intestine, exposure to C12 -C18 fatty acids resulted in conversion of the pro-micelle to a stable micelle that effectively delivered the pharmaceutically active agent to the systemic circulation. The membrane could be further encapsulated with a film coating or an enteric coating to provide a minicapsule. They could be used to deliver acid labile molecules such as insulin and other peptides by oral route and drugs showing inadequate oral absorption. Owen et al. provided a highly stable w/o microemulsion which readily converted to an o/w emulsion by the addition of aqueous fluid [113]. Proteins and peptides could be stored for long periods of time at room temperature and above by using the w/o microemulsion. When required for use aqueous fluid was added which converted the microemulsion to an o/w emulsion and released the protein. US Patent 5688761 described the extension of the above mentioned work in which the same assignee (LDS Technologies, Inc) had included high purity short chain monoglyceride surfactant as the preferred low HLB surfactant after finding that the use of C9-13 monoglycerides as the low HLB surfac-
tant enhanced the uptake of the active material upon administration [114]. Desai described a microemulsion formulation for oral administration, in which a liquid polyol solvent (propylene glycol or polyethylene glycol) and lipid cosolvent containing a proteinaceous medicament, e.g., insulin formed a microemulsion in the gastrointestinal tract at sites of absorption i.e. villi of the intestinal tract [115]. A vital ingredient in the formulation was the protease inhibitor which inhibited or prevented the degradation of the proteinaceous material. Earlier preparations contained ethanol which might cause protein denaturation. Poli et al. presented compositions in the form of microemulsions or liposomic dispersions for the transmucosal administration of therapeutic proteins or peptidic substances [116]. They contained in addition a thermosetting agent (Pluronic F127) which differentiated them from the known liposomic or microemulsified compositions. The composition had a low viscosity at room temperature which helped in the distribution of finely absorbed divided product on a larger surface and the viscosity increased on reaching the mucous as a result of structural change took place as a function of the body temperature. Ekwuribe et al. prepared hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin [117]. Microemulsion described was w/o type and had a HLB value between 3 and 7. In one particular aspect, the composition comprised insulin covalently coupled with a polymer, a linear polyalkylene glycol moiety and a lipophilic moiety, wherein the insulin, the linear polyalkylene glycol moiety and the lipophilic moiety are conformationally arranged in relation to one another such that the insulin in the composition had an enhanced in vivo resistance to enzymatic degradation, relative to insulin alone. HLB value of less than 7 provided a stable formulation for incorporating free form insulin and/or insulin conjugates suitable for oral administration. The microemulsion compositions could also be employed for non-therapeutic purposes, e.g., diagnostic. 3.1.4.1. Cyclosporine Delivery Cyclosporine delivery has remained a challenge for the formulation scientists. It is an immunosuppressive agent and is widely used in recipients of organ transplants and in various autoimmune diseases. It exerts potent immunosuppressive activity by inhibiting the growth and differentiation of T cells. The inherent insolubility of the cyclosporine provides the major hurdle for the low and variable bioavailability and there is variability in inter- and intra-patient dose response and low formulation stability during storage. It is, therefore, necessary to monitor blood/blood-serum levels of patients receiving cyclosporine therapy at regular and frequent intervals which is time consuming and inconvenient and adds to the overall cost of therapy. Due to poor bioavailability, higher doses may be needed which may result in undesirable adverse side effects such as nephrotoxicity and renal side effects which can be troublesome and may lead to an ineffective therapy. On reviewing general and patent literature it was found that a lot of researchers have endeavoured to make effective delivery
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systems for cyclosporine which can provide a suitable uniform dosage and appropriate bioavailability. Initially, cyclosporine was commercially available as a cyclosporine drink solution which provided an average absolute bioavailability of 30% only, with marked variation. The commercial product that had been sold under the name Sandimmune (Sandoz Ltd.) was made according to US Patent 4388307 [118]. The Sandimmune formulation contained cyclosporine in olive oil with the surfactant Labrafil and ethanol. However, the resulting liquid formulation was administered as an aqueous dilution (solution or emulsion) which was not convenient for the subject and might provide a non-uniform dosage for oral administration. In Sandimmun soft capsule a large amount of ethanol was used as a cosurfactant in order to solubilize the cyclosporine. However, since ethanol permeates the gelatin shell of the capsule and is volatile, its content may greatly vary during storage and may in turn result in crystallization of the cyclosporine which may lead to variation in the bioavailability. Sandoz Ltd. introduced an improved formulation later under the trademark Neoral according to the composition disclosed in US Patent 5342625 [119]. The Neoral formulation was a microemulsion pre-concentrate which contained cyclosporine in an anhydrous oily vehicle, medium chain triglycerides, surfactants, glycerol and alcohol which exhibited better and more consistent bioavailability. The preparation showed that cyclosporin bioavailability was almost not affected by food, bile secretion, etc. Therefore, frequent monitoring of the plasma level of patient was not needed, and hence was a remarkable improvement. A recent patent assigned to Novartis AG was concerned with the delivery of cyclosporines (excluding cyclosporine A) [120]. It included microemulsions and microemulsion pre-concentrate composition comprising of a hydrophilic component, lipophilic component containing cyclosporine and hydrophilic surfactant. The hydrophilic phase comprised of C1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol (e.g. Transcutol , Glycofurol); or 1,2-propyleneglycol. The composition upon dilution with adequate water spontaneously produced an o/w microemulsion having an average particle size of less than about 0.15 microns. The compositions permitted the preparation of solid, semi-solid and liquid preparations containing a cyclosporine in sufficiently high concentration which allowed convenient oral administration while at the same time achieving improved efficacy., e.g. in terms of bioavailability characteristics and there was reduced intra and inter individual variability. The compositions were non-alkanol based, e.g. which may be free or substantially free of ethanol. Earlier ethanol based formulations presented a number of problems. Evaporation of the ethanol, e.g. from capsules or from other forms, e.g. when opened, resulted in the development of a cyclosporine precipitate. Encapsulation of cyclosporine in soft gelatin encapsulated form necessitated packaging in an air-tight compartment, for example an air-tight blister or aluminiumfoil blister-package. This in turn rendered the product both bulky and more expensive to produce. Their compositions eliminated or reduced the packaging difficulties which were encountered with alkanolic compositions. In their earlier patent, the assignee had described a microemulsion pre-
concentrate composition comprising a cyclosporine, 1,2propylene glycol, a mixed mono-, di-, tri-glyceride and a hydrophilic surfactant [121]. They claimed a transesterification product of corn oil and glycerol (Maisine ) comprising a) a free glycerol content of less than 10%, b) less than 1% of palmitic acid and stearic acid mono-, di- and tri-glycerides; and c) 85% or more of linoleic acid and oleic acid mono-, di- and tri-glycerides all parts by weight which they didnt claim in their previous patent [122]. Further earlier the same assignee claimed an o/w microemulsion and microemulsion concentrate for the delivery of Cyclosporine A [123, 124]. The microemulsion had a particle size of less than 2000A while the microemulsion concentrate upon dilution with water spontaneously formed microemulsion which also had a particle size of less than 2000 A. Novartis AG in US Patent 5866159 described a microemulsion pre-concentrate of cyclosporin A comprising a hydrophilic component, triglyceride lipophilic component and polyoxyethylene glycolated natural or hydrogenated vegetable oil surfactant (Cremophor RH40, Cremophor RH60, Cremophor EL, etc.) [125].The composition upon dilution to 5 parts by weight of water spontaneously formed an o/w microemulsion having average particle size of less than about 200 nm. Use of alkanols, e.g. ethanol, as hydrophilic phase was less preferred. In an especially preferred embodiment the hydrophilic phase of compositions would consist of Transcutol, Glycofurol and/or 1,2-propylene glycol. Effective cyclosporin dosaging with concomitant enhancement of resorption/bioavailability levels, as well as reduced variability in resorption/bioavailability levels could be achieved both for individual patients receiving cyclosporin therapy as well as between individuals. Novartis AG in US Patent 7205279 described a microemulsion pre-concentrate comprising a hydrophilic phase which comprises dimethylisosorbide and/or a lower alkyl alkanoic ester, a lipophilic phase, and a surfactant for the delivery of cyclosporine and lactam macrolide [126]. The composition could also be in the form of microemulsion. The compositions provided good bioavailability and reduce variability in inter- and intra-patient dose response. Novartis AG had been granted a patent which described a cyclosporine containing composition in the form of a capsule comprising a polyoxyethylene sorbitan fatty acid ester, a reaction product of a natural or hydrogenated castor oil and ethylene oxide, a sorbitan fatty acid ester, and ethanol [127]. Mulye described an approach to deliver cyclosporine in a carrier comprising a fatty acid solubilizer having 6-22 carbon atoms and a non-ionic surfactant (HLB value greater than 10) which form an emulsion (emulsion or microemulsion) on exposure to water [128]. The inventor had suprisingly found that the use of a carrier system comprising a non-ionic surfactant in conjunction with a cyclosporin solubilizing agent consisting of C6-C22 fatty acids overcame the problems of limited solubility and resulting bioavailability associated with cyclosporin. Bhalani and Patel described a polar lipid self-emulsifying drug delivery system (PLSEDDS) of cyclosporine which instantly forms a fine emulsion when brought into contact with an aqueous medium [129]. The composition consisted
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of cyclosporine dissolved in a polar lipid, such as a medium chain monoglyceride of C6-C12 fatty acids having a monoglyceride content of at least 50% and a surfactant. They had found that medium chain monoglyceride as a component prevented crystallization of cyclosporine under storage conditions and cyclosporine A exhibited superior selfemulsification ability when dissolved in certain polar lipids as mentioned above. The encapsulated dosage form of this composition did not require a hydrophilic component (like ethanol, propylene glycol, or polyethylene glycol) which require specialized packaging, such as aluminum foil blister. Formulation could be inexpensively packaged such as in glass or OHD polyethylene bottles. The same inventors in their next patent provided PLSEDDS of lipophilic drugs in addition to cyclosporine dissolved in a polar lipid as mentioned earlier and containing surfactants and triglycerides [130]. Naicker et al. provided microemulsion or microemulsion preconcentrate of cyclosporine analogs that are structurally similar to cyclosporine A consisting of Vitamin E TPGS (Vitamin E-alpha-tocopheryl polyethylene glycol 1000 succinate), medium chain triglyceride oil, an emulsifier and ethanol [131]. The formulations provided superior drug bioavailability and reduced adverse effects. Chakravorty et al. described a self emulsifiable formulation consisting of cyclosporine, hydrophilic agent, lipophilic agent, surfactants, antioxidant and preservative [132]. Lipophilic system consisted of a medium chain triglyceride of caprylic acid and capric acid. Labrasol served as a surfactant, which was combined with other selected surfactants, like cremophor RH 40 and/or polysorbate 80. The formulation was filled in a soft-gelatin shell capable of rupturing in less than 12 minutes to provide quick release of the formulation in the upper part of the gastrointestinal tract. Domb provided a dispersible concentrate for the administration of a cyclosporine which included a hydrophilic solvent comprising a lower alkyl ester of hydroxyalkanoic acid or a lower alkyl ester of N-alkyl pyrrolidone and surfactant [133]. Surfactant was preferably a combination of a surfactant with high HLB of at least about 8 and a surfactant with low HLB of less than about 5. The characteristic feature of the concentrate was that it formed, upon contact with an aqueous solution, particles of a size of less than about 100 nm. Other ingredients were optional, such as a fatty acid ester such as tricaprin, a phospholipid, and an ethoxylated fat such as cremophor. The ethoxylated fat could be optionally substituted for the surfactant. Their formulations did not require stabilizers, such as anti-oxidants, for good stability. They hypothesized that the excellent stability compared to some of the earlier formulations was due to the use of hydrophilic solvents such as ethyl lactate. Ethyl lactate is miscible in both organic and inorganic solvents, since it is more hydrophobic than ethanol and has higher storage stability than ethanol owing to latters high volatility. Egbaria et al. taught a pharmaceutical composition comprising a spontaneous emulsion of cyclosporine, ethanol, polyoxyethylene glycerol trioleate, and an oil component [134]. A method for their preparation involved dissolving cyclosporine in ethanol. Then polyoxyethylene glycerol trioleate and an oil component were added, mixed and
diluted in an aqueous media to form a spontaneous emulsion. Polyoxyethylene glycerol trioleate was used as a surfactant which is non-toxic and well tolerated physiologically. The formulation provided a self-emulsifying delivery system in which the droplets are preferably from 50 to 150 nm and higher bioavailability was achieved. Meinzer et al. provided oil-free pharmaceutical compositions containing cyclosporinA [135]. A hard gelatin capsule dosage form containing cyclosporin A in a mixture with a surfactant of HLB value of at least 10 and hydrophilic phase being a polyethylene glycol and/or a lower alkanol provided that any lower alkanol, if present, is less than 12% of the total weight of the composition excluding the hard gelatin capsule weight. Their earlier patent was similar except in that they had specifically claimed a polyethyloxylated castor oil having an HLB value of at least 10 instead of a surfactant of HLB value of at least 10 [136]. They found that the compositions were compatible with tenside materials, e.g. bile salts, present in the gastrointestinal tract and were fully dispersible in aqueous systems comprising such natural tensides and are capable of providing microemulsion systems in situ which were stable and do not exhibit precipitation. Stuchlik et al. described cyclosporine compositions in which the concentration of cyclosporine was higher than 10% and provided high bioavailability [137]. Polar solvents had been omitted in the compositions which might cause compatibility problems with the capsule shell. The carrier was composed of partial esters of C16-22 fatty acids with a glycerol derivative selected from diglycerol to decaglycerol and partial esters of C8-16 fatty acids with pentaglycerol to pentadecaglycerol in mutual weight ratios of 1:1. Singh et al. taught in US Patent 6187747 substantially alcohol free composition of cyclosporine which comprised a cyclosporine in a hydrophilic carrier medium comprising propylene glycol, esters of propylene glycol with C4 to C12 fatty acids and polyoxyethylene hydrogenated castor oils [138]. On dilution with the gastrointestinal fluids the hydrophilic end of the surfactant and the cosurfactant were oriented towards hydrophilic environment of gastrointestinal fluid and the drug molecules were entrapped in the hydrophobic portions of the surfactant micelles. The drug was released leading to improved absorption, thus providing an increased and less variable bioavailibility. In their later patent they have broadened the claim by extending the percentage range of propylene glycol, esters of propylene glycol and polyoxyethylene hydrogenated castor oils [139]. Hong et al. taught a solid-state microemulsion of cyclosporin prepared by dispersing of cyclosporin microemulsion in enteric carrier [140]. The carrier prevented the release of cyclosporin in the acidic condition, while allowing a rapid release in the upper part of the small intestine thereby forming the microemulsion. The composition could maintain the plasma therapeutic level of cyclosporine for about 1 day by only once daily dosing. Hong et al. developed a cyclosporine containing microemulsion preconcentrate, which comprised lipophilic solvent, surfactant and oil [141]. Lipophilic solvent was typically comprised of alkyl ester of polycarboxylic acid
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(e.g. triethyl citrate, tributyl citrate) and/or carboxylic acid ester of polyols (e.g. triacetin). They reported that using lipophilic solvent was advantageous instead of hydrophilic solvent which causes pharmaceutical instability and can overcome the various problems of the prior formulations. Lipophilic solvents used in the invention were odorless and colorless oils in liquid state, and had high boiling point of more than 250C. They did not volatilize at the condition of high temperature during the procedure for soft capsule preparation as well as during storage at room temperature, and therefore, could ensure the stability of preparation comprising them. Moreover, they did not show such severe hygroscopic property as glycols showed, did not dissolve the gelatin shell, and did not induce the compositional change due to non-volatility and non-permeability for gelatin shell. Sherman described pharmaceutical compositions in the form of an emulsion preconcentrate or microemulsion preconcentrate comprising cyclosporine, acetylated monoglyceride (Myvacet) as lipophilic solvent, a surfactant, and optionally a hydrophilic solvent [142]. In comparison to other ingredients used as lipophilic solvent in some of the previous formulations, they found that acetylated monoglycerides offered various advantages such as low cost, good solvent properties for cyclosporines, thus reducing the amount of lipophilic solvent required and/or reducing the need for a hydrophilic co-solvent to maintain the cyclosporine in a stable solution and ready miscibility with preferred hydrophilic co-solvents such as polycarbonate and ready dispersibility into emulsions or microemulsions upon inclusion of a suitable surfactant. In his earlier patent, the inventor described a pharmaceutical composition in the form of a microemulsion preconcentrate comprising a cyclo-sporine dissolved in a solvent system comprising of a hydrophobic component, a hydrophilic component, and a surfactant, wherein either the hydrophobic component was selected from tocol, tocopherols, tocotrienols, and derivatives thereof, or the hydrophilic component was selected from propylene carbonate or polyethylene glycol having an average molecular weight of less than 1000 [143]. In a subsequent patent, the same inventor taught pharmaceutical compositions in the form of an emulsion preconcentrate or microemulsion preconcentrate of cyclosporine comprising propylene carbonate as hydrophilic solvent, glycerides as lipophilic solvent, and a surfactant [144]. The disclosed lipophilic solvents such as Vitamin E in his earlier patent were relatively expensive. He found that when propylene carbonate was used as hydrophilic solvent, excellent emulsion preconcentrate and microemulsion preconcentrates could be made using relatively inexpensive glycerides as lipophilic solvent, and without the use of ethanol. Kim et al. described pharmaceutical composition containing cyclosporine, an oil component, a hydrophilic cosurfactant consisting of propylene carbonate or a mixture of propylene carbonate and polyoxyethylene-polyoxypropylene block copolymer (pluronics, poloxamers), and a surfactant [145]. The use of the above mentioned hydrophilic cosurfactant provided a solubilizing effect sufficient for cyclosporine and also provided some advantages that it did not cause the change in capsule appearance and the precipitation of cyclosporine due to the change in solvent content, reduced the manufacturing cost to provide an economical effect and
does not have any toxicity problem of the solvent in comparison to the soft capsule using ethanol, transcutol, propylene glycol, glycofurol, dimethylisosorbide, etc., in the prior compositions. The composition could be dissolved in an external phase such as water, artificial gastric juice and intestinal juice, etc. to form a self-emulsion with mild stirring and therefore, by appropriately adjusting the constitutional ratio of each component the diameter of particles in the inner phase of the emulsion formed could be controlled to 100 nm or less. The composition was suggested to be formulated into the oral preparations such as soft capsules, hard capsules sealed with gelatin bending at the conjugated portion, oral liquid preparations, etc. The invention of Woo was concerned with a microemulsion concentrate containing cyclosporine as an active ingredient, dimethylisosorbide as a cosurfactant, oil and a surfactant where cyclosporine, dimethyl isosorbide, oil and surfactant were present in the ratio of 1:1-5:1-5:2-10 by weight [146]. The composition was suitable for the formulation of a soft capsule for oral administration. Since dimethylisosorbide has no membrane permeation property, the soft capsule preparation was stable in comparison with the soft capsules containing ethanol, propylene glycol, transcutol, glycofurol, etc., as a cosurfactant in the prior disclosures. Furthermore, appearance and composition content of the soft capsule according to the present invention were not changed. Earlier, the same inventor provided a cyclosporine soft capsule composition comprising cyclosporine as an active ingredient, dimethylisosorbide as a cosurfactant, components of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride (e.g. Nikkol VF-E, Miglyol 812) as an oil component, and a surfactant having an HLB value of 10 to 17 [147]. Another patent granted to the same inventor described a cyclosporine containing soft capsule composition which comprised cyclosporine as an active ingredient, polyethylene glycol having a molecular weight of 200 to 600 as a cosurfactant, a mixture of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component, and a surfactant having HLB value of 10 to 17 [148]. Polyethylene glycol is non-volatile, does not permeate the gelatin membrane of the soft capsule, and has a high solubility for cyclosporine and is therefore advantageous for administration of the composition in a soft capsule dosage form. 3.2. Parenteral Delivery The formulation of lipophilic and hydrophobic drugs into parenteral dosage forms has proven to be difficult. O/w microemulsions are beneficial in the parenteral delivery of sparingly soluble drugs where the administration of suspension is not desirable. They provide a means of obtaining relatively high concentration of these drugs which usually requires frequent administration. Other advantages are that they exhibit a higher physical stability in plasma than liposomes or other vesicles [149] and the internal oil phase is more resistant against drug leaching. Several sparingly soluble drugs have been formulated into o/w microemulsion for parenteral delivery [31, 149-156]. Microemulsions can
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also be used as intravenous delivery systems for the fat soluble vitamins and lipids in parenteral nutrition [156]. Dennis et al. patented an intravenous microemulsion delivery system for water insoluble or sparingly water soluble drugs that comprised an oil phase comprising the drug, a long polymer chain surfactant (e.g. lecithin, gelatin casein, tweens, macrogol ethers, etc.) component and a short fatty acid surfactant (e.g. stearic acid, glyceryl monostearate, sorbitan esters, etc.) component and an aqueous phase [157]. The droplet size ranged from 10-100 nm. They had found the composition to be useful for propofol, a short-acting intravenous anesthetic. Micromulsion would emulsify or partition propofol into the non-aqueous phase and preclude (or markedly reduce) stinging and allow painless injection. Dennis et al. in their invention taught a intravenous microemulsion delivery system comprising a long polymer chain surfactant component and a short fatty acid surfactant component, and an aqueous phase, wherein the amounts of the long chain polymer and short chain fatty acid surfactant components were selected to provide for spontaneous formation of thermodynamically stable microemulsion droplets of the oil phase having a particle size from 10-100 nm and the interfacial tension of the drug with the emulsifier combination was less than 0.1 dynes per cm [158]. This work was an extension of an earlier patent granted to the same inventors [157]. Microemulsions are generally not dilutable with aqueous fluids, such as certain bodily fluids and buffer solutions, and form emulsions upon contacting such fluids. Various microemulsions are also sensitive to temperature and are not stable outside of room temperature conditions. US Patent 6245349 provided drug delivery compositions in both concentrated and diluted forms for use as vehicles in the administration of various active agents [159]. The concentrated drug delivery compositions were formulated with a phospholipid component, a component selected from propylene glycol or certain polyethylene glycol compounds, a high HLB surfactant, and the drug component, with water and/or an optional oil component. The concentrated drug delivery compositions could be diluted with an aqueous fluid to form an o/w microemulsion. These o/w microemulsions were characterized by their small particle size and their wide range of temperature stability, typically from about -20o50oC. They could be administered by intravenous, intraarterial, intrathecal, intraperitoneal, intraocular, intraarticular, intramuscular or subcutaneous injection. According to the invention of the Wretlind et al. parenteral administration of water-insoluble active agents was enhanced when the agents were administered in the lipoid phase of a carrier microemulsion [160]. The microemulsion comprised of a finely dispersed lipoid in an aqueous phase with a mean particle size below 1 micron. Higher concentration of the agent (diagnostic or therapeutic) could be achieved and hence a lower dose whereby a rapid onset of the pharmacological effect was accompanied by a reduced incidence of injury to body tissues. As the agents were present in a dissolved state in the hydrophobic phase, there was no need of affecting the pH or the osmotic pressure of the aqueous phase. Because of this, the method of adminis-
tration according to the invention would cause a lower occurrence of injuries to the body tissues. US Patent 7157099 described stable, biologically compatible w/o microemulsions, for the sustained release by parenteral administration of hydrophilic active ingredients [161]. Microemulsions could be formulated particularly for peptide active ingredients (LHRH analogs such as Leuprolide acetate, Goserelin, Triptorelin, Somatostatin or its analogs such as Octreotide and Lanreotide acetate, etc.) or biologically active oligo- or polysaccharides (unfractioned heparin or low molecular weight heparins), which provides protection against immediate attack by the hydrolytic enzymes as well as sustained release to avoid repeated administrations. The microemulsions consisted up to 20% of an internal hydrophilic aqueous phase containing the active ingredient, 30 to 98% of a hydrophobic external phase and up to 50% of a surfactant alone or in admixture with a cosurfactant. Another technology already used for the sustained release of peptides involved the use of bioerodible polymers like polymers based on glycolic acid and lactic acid [162]. Drawbacks of using polymers include their higher cost and the issues of environmental impact and safety of the pharmaceutical formulation as organic, in particular chlorinated, solvents are used during their preparation. Also, these microemulsion formulations did not cause persistent granulomas which were reabsorbed during the time in which the medicament was effective and did not induce local ulcerogenicity. Vigne et al. disclosed microemulsions suitable for parenteral administration of fat soluble vitamins (vitamins E, A, D, and K) and hydrophobic drugs [163]. The microemulsions were comprised of a naturally occurring amphipatic substance and a hydrophobic lipid along with the active ingredient and were size selected for 30-100 nm pseudomicelles. According to them, the composition had the unique property of delivering fat soluble substances to the plasma in a form and distribution which mimicked the natural uptake in normal subjects. 3.3. Topical Delivery Microemulsion systems are now being investigated zealously for topical delivery which is evident from the numerous publications coming up every year. They have been reported to enhance the transdermal permeation of drugs significantly compared to conventional formulations such as solutions, gels or creams [164,165]. They are able to incorporate both hydrophilic (5-fluorouracil, apomorphine hydrochloride, diphenhydramine hydrochloride, tetracaine hydrochloride, methotrexate) and lipophilic drugs (estradiol, finasteride, ketoprofen, meloxicam, felodipine, triptolide) and enhance their permeation [18-22, 166-170]. Since the microemulsion is a multicomponent system and its formation requires high surfactant concentration, the skin irritation aspect must be considered especially when they are intended to be applied for a longer period. Several plausible mechanisms have been proposed to explain the advantages of microemulsion for the transdermal delivery of a drug: 1. A large amount of drug can be incorporated in the formulation due to the high solubilizing capacity that
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might increase thermodynamic activity towards the skin [171]. 2. The permeation rate of the drug from microemulsion may be increased, since the affinity of a drug to the internal phase in microemulsion can be easily modified to favour partitioning into stratum corneum, using different internal phase, changing its portion in microemulsion [172]. The surfactant and co surfactant in the microemulsions may reduce the diffusional barrier of the stratum corneum by acting as penetration enhancers [21]. The percutaneous absorption of drug will also increase due to hydration effect of the stratum corneum if the water content in microemulsion is high enough [173].
effective delivery systems. Microemulsions have emerged as a promising dosage form for ocular use [176]. Bowman et al. disclosed sustained release emulsions (macroemulsions and microemulsions) in which particles of the dispersed phase were dispersed and stably maintained in physical separation by lightly crosslinked, water swellable polymers (carboxyvinyl polymers, polyvinyl pyrolidone, etc.) present in an aqueous polymeric system formulated for administration to the eye in drop or ribbon form [23]. Medicament was dissolved in dispersed phase and was delivered over a sustained release period. Rather than using large quantities of the polymer, the invention relied on including an amount of the polymer sufficient to stably maintain that physical separation of the particles of the disperse phase of the emulsion within the aqueous polymeric system. The advantages of the invention included enhanced bioavailability of the sparingly soluble drug in water, inhibition of the tendency of oily medicaments to separate and/or agglomerate in aqueous media and sustained action. Chloramphenicol, an antibiotic used in the treatment of trachoma and keratitis, in the common eye drops hydrolyzes easily. Lv et al. investigated chloramphenicol microemulsion composed of Span 20, Tween 20, isopropylmyristate and water as potential drug delivery systems for eye drops [177]. Chloramphenicol was entrapped in the o/w microemulsion free of alcohol. Its stability was determined in the accelerated experiments of three months. The authors revealed that the content of glycol (main hydrolysis product) in the microemulsion formulation was much lower than that in the commercial eye drops at the end of the accelerated experiments. Thus, a remarkable increase in the chloramphenicol stability was observed in the microemulsion formulations. Fialho et al. prepared microemulsion based dexamethasone eye drops which showed better tolerability and higher bioavailability [178]. The formulation showed greater penetration in the eye which allowed the possibility of decreasing the number of applications per day. This might be useful in achieving improved patient compliance. Habe et al. formulated water-continuous microemulsions for ocular application of pilocarpine [179]. in vitro Studies showed a prolonged pilocarpine release from the microemulsions with lecithin. The authors found microemulsions to be favourable for ophthalmological use. 3.5. Nasal Delivery Microemulsions are now being studied as a delivery system to enhance uptake across nasal mucosa. Addition of a mucoadhesive polymer helps in prolonging the residence time on the mucosa. Nasal route for administration of diazepam might be a useful approach for the rapid onset of action during the emergency treatment of status epilepticus. For this microemulsion was formulated comprising of ethyl laurate (15%), Tween 80:propylene glycol:ethanol at 1:1:1 weight ratio (70%) and water (15%). The nasal absorption of diazepam was found to be fairly rapid at 2 mg kg-1 dose with maximum drug plasma concentration reached within 2-3 min. The bioavailability (0-2 h) after nasal spray compared to i.v. injection was about 50% [24].
3.
4.
Due to the small droplet size and large amount of inner phase in microemulsions, the density of droplets and their surface area are assumed to be high. Therefore, droplets settle down to close contact with the skin providing high concentration gradient and improved drug permeation. Moreover, low surface tension ensures good contact to the skin. Also, the dispersed phase can act as a reservoir making it possible to maintain an almost constant concentration gradient over the skin for a long time [19]. The liquid, transparent, multicomponent systems according to the invention of Muller et al. contained the active agents in a solution of an oily and optionally an aqueous component in the presence of surfactants and cosurfactants [174]. Under certain conditions, the cosurfactants can serve as oil components or vice-versa. The efficacy of the active agents applied in the form of the multicomponent systems according to the invention was much better than that of active agents applied in the form of known multicomponent systems. The multicomponent systems could be used in pharmaceutical products for cutaneous, peroral, vaginal and parenteral administration of pharmaceutical active agents. The invention of Protopapa et al. referred to depilatory preparations containing proteolytic enzymes solubilized in microemulsions, formed with lecithin, aliphatic hydrocarbon, alipathic alcohol and buffer solution (pH 7-9) to be applied for permanent enzymic depilation [175]. The invention introduced the use of microemulsions as a medium for the facilitated penetration of the enzymic activity in the epithelial cells of the skin. In addition, their invention referred to a depilation method that applied the preparations of microemulsion containing the enzyme alpha-chymotrypsin, or the enzyme trypsin, for the depilation of any type of skin (fatty-resistant or dry-sensitive). The application of these preparations provided more permanent depilation than the one resulting from other depilatory methods. 3.4. Opthalmic Delivery In conventional ophthalmic dosage forms, water soluble drugs are delivered in aqueous solution while waterinsoluble drugs are formulated as suspensions or ointments. Low corneal bioavailability and lack of efficiency in the posterior segment of ocular tissue are some of the serious drawbacks of these systems. Recent research efforts have therefore focused on the development of new and more
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3.6. Periodontal Delivery Periodontal disease is a collective term for a number of progressive oral pathological afflictions like inflammation and degeneration of the gums, periodontal ligaments, cementum and its supporting bone. It is a major cause of tooth loss. The invention of Brodin et al. included a novel pharmaceutical composition comprising local anaesthetic in oil form, surfactant, water and optionally a taste masking agent [180]. The composition was in the form of an emulsion or microemulsion and had thermoreversible gelling properties i.e. it was less viscous at room temperature than after introduction onto a mucous membrane of a patient. The surfactant in the formulation imparted the thermoreversible gelling properties. Preferred surfactants were Poloxamer 188, Poloxamer 407 and Arlatone 289. The composition could be used as a local anaesthetic for pain relief within the oral cavity in conjunction with periodontal scaling and root planning and overcame the problem with the existing topical products (jelly, ointment or spray) such as lack of efficacy due to inadequate depth of penetration, too short duration and difficulties in administration due to spread, taste etc. 3.7. Drug Targeting Drug targeting has evolved as the most desirable but elusive goal in drug delivery. By altering the pharmacokinetics and biodistribution of drugs and restricting their action to the targeted tissue increased drug efficacy with concomitant reduction of their toxic effects can be achieved. Drug targeting to diseased cells can be achieved by exploiting the presence of various receptors, antigens/ proteins on the cell membrane which may be uniquely expressed or over expressed in these cells as compared to the normal cells. Specific antibodies to the surface proteins and ligands for the receptors can be used to target specific cells. Submicron size range of these systems confers excellent opportunities to overcome the physiological barriers and enables efficient cellular uptake followed by intracellular internalization. 3.7.1. Cellular Targeting Nucleic acids delivered to cells are promising therapeutics. The invention of Monahan et al. included insertion of nucleic acid into a reverse micelle for cell delivery [181]. They referred w/o microemulsions to as reverse micelles. The reverse micelle had the property to compact the nucleic acid for easier delivery. To further enhance the delivery, other molecules such as a surfactant having a disulfide bond or a polyion might be added to the nucleic acid-micelle complex. Another advantage of the invention was the use of reverse micelles for gene delivery to the cells. The micelle containing the compacted polynucleotide could be utilized as a reaction vesicle in which additional compounds such as polycation could be added to the DNA. Additionally, the polynucleotide/reverse micelle system was used as a vesicle for template polymerization of the DNA or caging of the DNA in which the polycation was crosslinked. Another advantage was that the micelle might be cleaved under physiological conditions involved along the transfection (process of delivering a polynucleotide to a cell) pathway. Better recovery and purification of the bio-
molecules could be achieved by utilizing cleavable reverse micelles which was difficult earlier. The invention of Wheeler et al. was related to cell delivery of hydrophobic compounds in microemulsion carriers [182]. Microemulsion was comprised of a mixture of oil, a hydrophobic compound, and a polyethylene glycollinked lipid. The purpose of polyethylene glycol-linked lipid was to enhance the stability of the microemulsion compositions. The hydrophobic compound resided in an oil environment which was surrounded by a monolayer of a polar lipid. The polar head of the lipid faced outwards to provide compatibility with the external aqueous environment and the nonpolar tail faced the internal oil environment. A targeting moiety such as biotin, avidin, streptavidin or antibodies might be covalently or noncovalently attached to the lipid monolayer. The composition could also be used for diagnostic and therapeutic purposes. 3.7.2. Tumour Targeting Maranh ao suggested the utility of microemulsions as vehicles for the delivery of chemotherapeutic or diagnostic agents to neoplastic cells while avoiding normal cells [183]. They claimed a method for treating neoplasms, wherein neoplasms cells have an increased number of LDL (low density, lipoprotein) receptors compared to normal cells. The microemulsion comprised of a nucleus of cholesterol esters and not more than 20% triglycerides surrounded by a core of phospholipids and free cholesterol and contained a chemotherapeutic drug. Microemulsions were similar in chemical composition to the lipid portion of low density lipoprotein (LDL), but did not contain the protein portion. These artificial microemulsion particles incorporated plasma apolipoprotein E (apo E) on to their surface when they were injected in the bloodstream or incubated with plasma. The apolipoprotein E served as a linking element between the particles of the microemulsion and the LDL receptors. The microemulsions could then be incorporated into cells via receptors for LDL and delivered the incorporated molecules. Thus, higher concentration of anticancer drugs could be achieved in the neoplastic cells that have an increased expression of the receptors. In this way toxic effects of these drugs on the normal tissues and organs could be avoided. In human subjects, they observed no change in the plasma kinetics of the radioactively labeled microemulsion containing carmustine or cytosine-arabinoside thereby confirming that the incorporation of these drugs did not diminish the capacity of the microemulsion to incorporate apo E in the plasma and bind to the receptors. Shiokawa and coworkers reported a novel microemulsion formulation for tumour targeted drug carrier of lipophilic antitumour antibiotic aclacinomycin A (ACM) [184]. Their findings suggested that a folate-linked microemulsion is feasible for tumour targeted ACM delivery. The study showed that folate modification with a sufficiently long PEG chain on emulsions is an effective way of targeting emulsion to tumour cells. 3.7.3. Brain Targeting Intranasal administration confers a simple, practical, cost effective, convenient and noninvasive route of administration for rapid drug delivery to the brain [185-187]. It
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allows a direct transport of drugs to the brain circumventing the brain barriers [188, 189]. Vyas et al. prepared mucoadhesive microemulsion for an antiepileptic drug clonazepam [25]. The aim was to provide rapid delivery to the rat brain. Brain/blood ratio at all sampling points up to 8h following intranasal administration of clonazepam mucoadhesive microemulsion compared to i.v. was found to be 2fold higher indicating larger extent of distribution of the drug in the brain. CURRENT & FUTURE DEVELOPMENTS The full potential of microemulsion systems is yet to be realized. A lot of innovations are expected to come in the field of microemulsion technology. The role of microemulsion systems is of paramount importance in providing novel solutions to overcome the problems of poor aqueous solubility of highly lipophilic drug compounds and provide high, more consistent and reproducible bioavailability. Furthermore, these formulations can be easily scaled up which is important from industrial standpoint considering the relative cost of commercial production. In addition to oral drug delivery, a lot of topical products employing the microemulsion technology are likely to emerge. This is significant not only from the view point of drug delivery but also from the huge and lucrative cosmetic market prospects. Microemulsions can also be used to achieve drug targeting however challenges remain, primarily because of the layers of barriers that these systems need to overcome to reach to the target. Recent research work is focused on the production of safe, efficient and more compatible microemulsion constituents which will further enhance the utility of these novel vehicles. A considerable amount of work still needs to be performed to characterize the physicochemical behaviour of the microemulsions. Despite the caveat associated with this therapeutic system, the current scientific interest seems to be directed at recognizing its full potential as a novel drug delivery tool. ACKNOWLEDGEMENTS One of the authors, A. Azeem is highly grateful to the University Grants Commission, Government of India for providing financial assistance in the form of research fellowship. REFERENCES
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Recent Patents on Drug Delivery & Formulation 2008, 2, 238-257

Microemulsions: A Novel Approach to Enhanced Drug Delivery

Microemulsions in Drug Delivery

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Comparison of Microemulsion with Conventional Emulsion

Phases Preparation Viscosity

Microemulsions in Drug Delivery

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Microemulsions in Drug Delivery

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Microemulsions in Drug Delivery

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Bioavailability Enhancement of Some Drugs Using Microemulsion Technology

Fig. (4). Functioning of the polymer matrix dispersed in a SMEDDS formulation.

Microemulsions in Drug Delivery

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Microemulsions in Drug Delivery

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Microemulsions in Drug Delivery

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

Microemulsions in Drug Delivery

Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3

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