Microemulsion as a Novel Carrier for Vaginal Delivery- A Review

 

Dhara Patel*, Nimisha Patel, Anjali Patel, Jayvadan Patel, Anita Patel, Manish Patel

Department of Pharmaceutics, Nootan Pharmacy College, Visnagar-384315, Gujarat, India.

*Corresponding Author E-mail: dhara.patel032@gmail.com

ABSTRACT:

The novel carriers have been exploited through almost all the routes of administration. Many newer carriers are evolving with the advent of technology and the demand of targeted delivery like microemulsions. Microemulsions are clear, transparent, thermodynamically stable dispersions of oil and water, stabilized by an interfacial film of surfactant frequently in combination with a co-surfactant with a droplet size usually in the range of 20-200 nm. Microemulsions act as supersolvents of drug.  They can solubilize hydrophilic and lipophilic drugs including drugs that are relatively insoluble in both aqueous and hydrophobic solvents. They have been used to improve the oral bioavailability of various poorly soluble drugs. 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. While microemulsions are used in several fields, this article focuses on the reported investigations for vaginal applications which exhibit minimal systemic absorption.

 

 

INTRODUCTION:

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.

Microemulsions are transparent liquid systems consisting of at least ternary mixtures of oil, water and surfactant and also sometimes a cosurfactant is needed for the formation of a thermodynamically-stable microemulsion. A transparent microemulsion is, in fact, heterogeneous (nanostructured) on a molecular scale and microemulsion domains fluctuate in size and shape and undergo spontaneous coalescence and break-up². They can exhibit water continuous and bicontinuous structures, with typical sizes ranging from about 10 to 100nm³. Drug containing microemulsions can be adsorbed onto solid particles which may be further formulated into solid dosage form to improve the bioavailability and solubility of drugs.

 

By using this concept Sangeeta V. et.al have developed a new dosage form that is microemulsion as solid dosage form (United States Patent 6280770). They used poorly bioavailable drug like testosterone propionate in their work, which gave good results⁴.

 

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). Microemulsions have very small droplet size because of small droplets provide better adherence to membranes and transport drug molecules in a controlled fashion. Microemulsions are easy to administer to children and to the people who have difficulty to swallow solid oral dosage forms. The key differences between ordinary emulsions (macroemulsions) and microemulsions are shown in Table 1.1 ^{5, 6}.

 

Types of microemulsion:

Three types ⁷

1. O/W microemulsion (direct microemulsion)

2. W/O microemulsion (indirect microemulsion)

3. Bicontinuous microemulsion

 

 

Table 1.1.: Comparison of microemulsion with conventional emulsion ^{5, 6}

 

Advantages of microemulsion:

1.      Easy to manufacture and scale-up ⁸.

2.      Improved drug solubility and bioavailability ⁸.

3.      This system is advantageous because of its wide applications in colloidal drug delivery systems for the purpose of drug targeting and controlled release ⁸.

4.      Microemulsions are thermodynamically stable system and the stability allows self-emulsification of the system whose properties are not dependent on the process followed ⁸.

5.      Microemulsions act as supersolvents of drug because they can solubilize hydrophilic and lipophilic drugs including drugs that are relatively insoluble in both hydrophilic and hydrophobic solvents⁹.

6.      The dispersed phase, lipophilic or hydrophilic (oil-in-water, O/W, or water-in-oil, W/O microemulsions) can behave as a potential reservoir of lipophilic or hydrophilic drugs, respectively. The drug partitions between dispersed and continuous phase, and when the system comes into contact with a semi-permeable membrane, the drug can be transported through the barrier and drug release with pseudo-zero-order kinetics can be obtained, depending on the volume of the dispersed phase, the partition of the drug and the transport rate of the drug⁹.

7.      The mean diameter of droplets in microemulsions is below 0.22 mm. They can be sterilized by filtration. The small size of droplet in microemulsions e.g. below 100 nm, yields very large interfacial area, from which the drug can quickly be released into external phase when absorption (in vitro or in vivo) takes place, maintaining the concentration in the external phase close to initial levels⁹.

8.      Microemulsion are thermodynamically stable because of thermodynamic stability, microemulsions are easy to prepare and require no significant energy contribution during preparation.

9.      Microemulsions have low viscosity compared to other emulsions9.Microemulsion as delivery systems can improve the efficacy of a drug, allowing the total dose to be reduced and also minimizing side effects of the drugs⁹.

10.    Microemulsion become unstable at low or high temperature but when the temperature returns to the stability range, the microemulsion reforms so the formation of microemulsion is reversible⁹.

 

Disadvantages of microemulsion based systems¹⁰:

1.      Use of a large concentration of surfactant and co-surfactant which may be toxic.

2.      Limited solubilizing capacity for high-melting drugs.

3.      Microemulsion stability is influenced by environmental parameters such as temperature and pH and these parameters change upon microemulsion delivery to patients.

 

Important characteristics of microemulsions ¹¹:

Particle size < 200 nm

Thermodynamically stable

Optically clear

Surface area increased

High solubilizing capabilities

 

Components of microemulsion system ¹²:

A large number of oils and surfactants are available but their use in the microemulsion formulation is restricted due to their toxicity, unclear mechanism of action and irritation potential. Oils and surfactant which will be used for the microemulsion preparation should be biocompatible, non-toxic, clinically acceptable, microemulsion. The excipients should be generally regarded as safe (GRAS).

 

1 Oil phase:

The oil component influences curvature by its ability to penetrate and swell the tail group region of the surfactant monolayer. Following is the list of oils which are mainly used for the formulation of micro emulsion:

·      Saturated fatty acid- lauric acid, myristic acid, capric acid

·      Unsaturated fatty acid- oleic acid, linoleic acid, linolenic acid

·      Fatty acid ester- ethyl or methyl esters of lauric, myristic and oleic acid.

 

The main criterion for the selection of oil is that the drug should have high solubility into oil. This will minimize the volume of the formulation to deliver the therapeutic dose of the drug in an encapsulated form.

 

2. Surfactants:

The role of surfactant in the formulation of microemulsion is to lower the interfacial tension and provide a flexible around the droplets. The surfactant should have appropriate lipophilic character to provide the correct curvature at the interfacial region. Generally, low HLB surfactants are suitable for w/o microemulsion, whereas high HLB (>12) are suitable for o/w microemulsion preparation.

 

 

Following are the different surfactants are mainly used for microemulsion- Tween 80 and Tween 20, Lauromacrogol 300, Lecithins, Labrafil M 1944 LS, plurol oleique, Aerosol OT, Labrasol.

 

3. Cosurfactants:

Cosurfactants are mainly used in micro emulsion formulation for following reasons:

·      They allow the interfacial film sufficient flexible to take up different curvatures.

·      Required to form micro emulsions over a wide range of composition.

·      Short to medium chain length alcohols (C3-C8) reduce the interfacial tension and increase the fluidity of the interface.

·      Surfactant having HLB greater than 20 often require the presence of co surfactants to reduce their effective HLB to a value within the range required for micro emulsion formulation.

 

Following are the different co surfactant mainly used for micro emulsion: sorbitan Manolete, sorbitan monosterate, propylene glycol, Capryol 90, Trans cutol and ethanol.

 

Preparation of microemulsions¹²:

Following are the different methods for the preparation of micro emulsion

- Phase titration method

- Phase inversion method

 

Phase titration method:

Microemulsions are prepared by the spontaneous emulsification method (phase titration method) and can be portrayed with the help of phase diagram. As quaternary phase diagram (four component system) is time consuming and difficult to interpret, pseudo ternary phase diagram is constructed to find out the different zones including micro emulsion zone, in which each corner of the diagram represents 100% of the particular components. Pseudo-ternary phase diagrams of oil, water, and co-surfactant/surfactants mixtures are constructed at fixed co surfactant/surfactant weight ratios. Phase diagrams are obtained by mixing of the ingredients, which shall be pre- weighed into glass vials and titrated with water and stirred well at room temperature. Formation of monophasic/ biphasic system is confirmed by visual inspection. In case turbidity appears followed by a phase separation, the samples shall be considered as biphasic. In case monophasic, clear and transparent mixtures are visualized after stirring; the samples shall be marked as points in the phase diagram. The area covered by these points is considered as the microemulsion region of existence.

Phase inversion method:

Phase inversion of microemulsion is carried out 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 ultimately affect drug release both in vitro and in vivo. For non-ionic surfactants, this can be achieved by changing the temperature of the system, forcing a transition from an o/w micro emulsion at low temperature to a w/o micro emulsion at higher temperatures (transitional phase inversion). During cooling, the system crosses a point zero spontaneous curvature and minimal surface tension, promoting the formation of finely dispersed oil droplets. Apart from temperature, salt concentration or pH value may also be considered. A transition in the radius of curvature can be obtained by changing the water volume fraction. Initially water droplets are formed in a continuous oil phase by successively adding water into oil. Increasing the water volume fraction changes the spontaneous curvature of the surfactant from initially stabilizing a w/o micro emulsion to an o/w micro emulsion at the inversion locus.

 

Microemulsion based vaginal preparations¹³:

Vaginal preparations are liquid, semi-solid or solid preparations intended for administration to the vagina to obtain a local effect. They contain one or more active substances. Several categories of vaginal preparations may be:

·        Pessaries,

·        Vaginal tablets,

·        Vaginal capsules,

·        Vaginal solutions, emulsions and suspensions,

·        Tablets for vaginal solutions and suspensions,

·        Vaginal semi-solid preparations,

·        Vaginal foams,

·        Medicated vaginal tampons.

 

Pessaries’:

Pessaries’ are solid, single-dose preparations and they have various shapes, usually ovoid, with a volume and consistency suitable for insertion into the vagina. They contain one or more active substances dispersed or dissolved in a suitable basis that may be soluble or dispersible in water or may melt at body temperature. Excipients such as diluents, adsorbents, surface-active agents, lubricants, antimicrobial preservatives and colouring matter may be added, if necessary.

 

Vaginal tablets:

Vaginal tablets are solid, single-dose preparations which are in the form of uncoated or film-coated tablets.

 

Vaginal capsules:

Vaginal capsules (shell pessaries) are solid, single-dose preparations. They are generally similar to soft capsules, differing only in their shape and size. Vaginal capsules have various shapes, usually ovoid. They are smooth and have a uniform external appearance.

 

Vaginal solutions, emulsions and suspensions:

They are supplied in single-dose containers. The container is adapted to deliver the preparation to the vagina. Vaginal solutions, emulsions and suspensions are liquid preparations intended for a local effect, for irrigation or for diagnostic purposes. They may contain excipients, for example to adjust the viscosity of the preparation, to adjust or stabilise the pH, to increase the solubility of the active substance(s) or to stabilize the preparation. The excipients do not adversely affect the intended medical action. Vaginal emulsions may show evidence of phase separation but are readily redispersed on shaking.

 

Semi-solid vaginal preparations:

Semi-solid vaginal preparations are ointments, creams or gels. They are often supplied in single- dose containers with a suitable applicator. Semi-solid vaginal preparations comply with the requirements.

 

Today, there is growing interest in the vaginal route of administration, which also avoids the hepatic first-pass effect. The vagina allows women to self-administer medication continuously for weeks or months at a time with a single application. Modern technology has yielded vaginal drug-delivery systems that provide optimized pharmacokinetic profiles. These characteristics make the vagina an excellent route for drug administration.

 

The first vaginal applied formulations were used to treat local bacterial and fungal infections and inflammations. Today the high fungicidal vaginal infections which require often a systemically treatment are very problematically. An advantage would be an effective topical or local treatment. Administration of local spermicides and cleansing products is also a current practice. The development of novel products for female health, comprising therapeutic substances such as peptides, proteins, antigens, or antisense oligonucleotides, necessitates the design of high performance intravaginal drug delivery systems. In the case of local treatment, it is challenging to design delivery systems providing high drug concentrations in the vagina for a prolonged period of time, while in the case of systemic treatment; the major challenge is to gain high drug bioavailability¹⁴. This route of administration offers advantages compared to other routes. Considerable progress has been made in this research area over the past few years and, at present, the anatomy and physiology, microflora and secretions of the vagina are well understood. To date, there are only a limited number of vaginal dosage forms available, although various possibilities are presently being explored.

 

The currently available vaginal delivery systems have limitations, such as leakage, messiness and low residence time, which contribute to poor subject or patient compliance.

 

However, despite all the advantages of a vaginal application, changes of the membrane during the menstrual cycle and postmenopausal must be taken into account. In postmenopausal women the reduced epithelial thickness may change the original absorption rates of drugs significantly¹⁵. During the last three decades considerable attention has been focused on the development of novel and controlled delivery systems providing a long-term therapeutic concentration of drugs following a single dose.

 

Beside novel drug loaded inserts which are on the market, hydrogel systems with higher retention time are existing. Many drug delivery systems are based on mucoadhesive polymers. Mucoadhesion is another version of the bioadhesion because the target is still the underlying tissue. These polymers are able to swell rapidly when placed in aqueous environment and therefore exhibiting a controlled drug release^16-19. Consequently, the therapeutic efficacy of locally acting drugs can be improved by their increased availability at the target membrane.

 

Rational designs of future formulations need to include attention to vehicle properties that optimize vaginal coating and retention. It should be taken into account that formulations interact with the vaginal fluids and cause changes in viscosity. The interactions depend upon the specific macromolecules which are the thickening agents for gels or important auxiliary agents in tablets. Therefore, these macromolecules, such as poly (acrylates), cellulose-derivatives, chitosan and many others, are very important excipients for future formulations.

 

Advantages of vaginal drug delivery:

Despite the fact that vaginal delivery is only available for females there are a number of advantages for the vaginal route of administration like:

·      Avoidance of hepatic first-pass metabolism is particularly advantageous for compounds that undergo a high degree of hepatic metabolism e.g. by the greater bioavailability of propranolol after vaginal administration compared with oral delivery²⁰.

·      Reduction in the incidence and severity of gastrointestinal side effects, as observed during the vaginal delivery of bromocriptine²¹.

·      Reduction in hepatic side effects of steroids used in hormone replacement therapy or contraception²².

·      It overcomes the inconvenience caused by pain, tissue damage and probable infection by parenteral routes.

·      Another advantage is the possible self-insertion and removal of the dosage form²³.

 

The potential benefits of vaginal drug delivery over oral include lower dosing and lower systemic exposure plus lower incidences of side effects while achieving the same pharmacodynamic effect. Avoiding the fluctuations resulting from daily intake may also lower the incidence of side effects. Side effects are identified as the most important factor associated with discontinuation of oral contraception. Lowering the incidence of side effects will increase the acceptability of a product and thus enhance patient compliance. Vaginal drug delivery can also allow for selective regional therapeutic administration, that is, local drug exposure where needed, producing little or no change in exposure throughout the rest of the body.

Limitation of vaginal drug delivery:

In addition to being gender specific, the vaginal route is less preferable in terms of convenience depending on the dosage form. Another disadvantage is the influence of the estrogen concentration on the permeability of the vaginal membrane, which can influence the pharmacokinetics of drugs designed for systemic action²⁴. The amount of vaginal fluid of an adult woman was reported to be in the range of 2–3 g/24 h and this amount is decreasing with increasing age. This volume may also affect the vaginal absorption of drugs. As a drug must be in solution before it can be absorbed the presence of a film of moisture will be an advantage but in contrast to this the presence of thick cervical mucus may present also a barrier to drug absorption.

 

Finally the pH of the fluid may affect the drug absorption too as it can be supposed that unionized forms will be preferable absorbed.

 

Characterization of microemulsions:

Microemulsions have been characterized using a wide variety of techniques. The characterization of microemulsions is a difficult task due to their complexity, variety of structures and components involved in these systems, as well as the limitations associated with each technique but such knowledge is essential for their successful commercial exploitation. Therefore, complementary studies using a combination of techniques are usually required to obtain a comprehensive view of the physicochemical properties and structure of microemulsions. At the macroscopic level viscosity, conductivity and dielectric methods provides useful information.

 

(A) Phase behavior studies²⁵:

Phase behavior studies are essential for the study of surfactant system determined by using phase diagram. Phase behaviour studies also allow comparison of the efficiency of different surfactants for a given application. In the phase behaviour studies, simple measurement and equipments are required. The boundaries of one-phase region can be assessed easily by visual observation of samples of known composition. The main drawback is long equilibrium time required for multiphase region, especially if liquid crystalline phase is involved.

 

(B) Scattering techniques for microemulsions characterization:

Small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), and static as well as dynamic light scattering are widely applied techniques for microemulsions. These methods are very valuable for obtaining quantitative informations on the size, shape and dynamics of the components. The major drawback of this technique is the dilution of the sample required for the reduction of interparticular interaction. This dilution can modify the structure and the composition of the pseudophases. Small-angle X-ray scattering techniques have been used to obtain information on droplet size and shape^26-30.

 

Static light scattering techniques have also been widely used to determine microemulsion droplet size and shape.  In these experiments the intensity of scattered light is generally measured at various angles and for different concentrations of microemulsion droplets. Dynamic light scattering, which is also referred as photon correlation spectroscopy (PCS), is used to analyse the fluctuations in the intensity of scattering by the droplets due to Brownian motion. The self-correlation is measured that gives information on dynamics of the system^31-35.

 

(C) Nuclear magnetic resonance studies:

The structure and dynamics of microemulsions can be studied by using nuclear magnetic resonance techniques. Self-diffusion measurements using different tracer techniques, generally radio labeling, supply information on the mobility of the components^36-39.

 

(D) Interfacial tension:

The formation and the properties of microemulsion can be studied by measuring the interfacial tension.  Ultra low values of interfacial tension are correlated with phase behaviour. Spinning-drop apparatus can be used to measure the ultra low interfacial tension⁴⁰.

 

(E) Viscosity measurements:

Viscosity measurements can indicate the presence of rod-like or worm-like reverse micelle^41,42. Viscosity measurements as a function of volume fraction have been used to determine the hydrodynamic radius of droplets, as well as interaction between droplets and deviations from spherical shape by fitting the results to appropriate models.

 

(H) Electron microscope characterization⁴³:

Transmission Electron Microscopy (TEM) is the most important technique for the study of microstructures of microemulsions because it directly produces images at high resolution and it can capture any co-existent structure and micro-structural transitions.

 

Applications⁴⁴:

Microemulsions in food

Parenteral delivery

Oral drug delivery

Topical drug delivery

Microemulsions in biotechnology

Brain targeting

 

CONCLUSION:

Microemulsions are transparent liquid systems consisting of at least ternary mixtures of oil, water and surfactant and also sometimes cosurfactants are needed for the formation of a thermodynamically-stable microemulsion. Microemulsions have been shown to be able to control drug release, increase bioavailability, increase solubility of poorly soluble drugs, and reduce patient variability. Microemulsions are differentiated from normal emulsions by their transparency, low viscosity and thermodynamic stability. Microemulsion can be used for cosmetic purpose and also for drug targeting. Now a day, researcher work is focused on the production of safe, efficient and more compatible microemulsion.

 

REFERENCES:

1.       Aungst BJ. Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism. Journal of Pharmaceutical Science. 82; 1993: 979-986.

2.       Zana R, Lang J, Frieberg SE, Bothorel (eds) Microemulsions: structure and dynamics. CRC, Boca Raton, FL, Ch 6. 1987.

3.       Biasia J, Clin B, Laolanne P: Friberg SE, Bothorel P (eds) Microemulsions: structure and dynamics. CRC, Boca Raton, FL, Ch 1. 1987  

4.       Majumdarshiv, Microemulsion as solid dosage form, Pharmainfo.net, Pharmaceutical blogs, 2009.

5.       Holm R et al. Examination of oral absorption and lymphatic transport of halofantrine in a triple- cannulated canine model after   administration in self- microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. European Journal of Pharmaceutical Science. 20; 2003: 91- 97.

6.       Pouton CW. Lipid formulation for oral administration of drugs: non- emulsifying, self- emulsifying and self- microemulsifying drug delivery systems. European Journal of Pharmaceutical Science. 11; 2000: S93- S98.

7.       Nairn JG, Gennaro AF. Solutions, emulsions, suspensions and extracts in Remington: The Science and Practice of Pharmacy. Lippincott Williams and Wilkins 2000; 20th ed: pp. 740-741.

8.       Ghosh PK, Murthy RS. Microemulsions: A potential drug delivery system. Current Drug Delivery. 3(2); 2006: 167-180.

9.       Vyas SP, Khar RK. Submicron emulsions in targeted and controlled drug delivery, Novel Carrier Systems; CBS Publishers and Distributors, New Delhi. 2002: 282 – 302.

10.     Shaji J, Reddy MS. Microemulsions as drug delivery systems, Pharma Times. 36 (7); 2004: 17 – 24.

11.     Deshpande SG et al. Intraarterial and intravascular drug delivery systems In Advances in Controlled and Novel Drug Delivery. Jain NK. CBS Publishers and Distributors, New Delhi. 2001: 182 – 183.

12.     Talegaonkar S et al. Microemulsions: a novel approach to enhanced drug delivery. Recent Patent Drug Delivery Formulation. 2; 2008: 238-257.

13.     European Pharmacopoeia, vaginal preparation, 1; 2005: 629-630.

14.     Bernkop-Schnurch A, Hornof M. Intravaginal Drug Delivery Systems: Design, Challenges, and Solutions. American Journal of Drug Delivery. 1(4); 2003: 241- 254.

15.     Furuhjelm M, Karlgren C, Carlstrom K. Intravaginal administration of conjugated estrogens in postmenopausal women. Int. J. Gynecol. Obstet. 17; 1980: 335-339.

16.     Genc L, Oguzlar C, Guler E. Studies on vaginal bioadhesive tablets of acyclovir. Pharmazie. 55; 2000: 297-299.

17.     Richardson JL, Trevor TI. Vaginal delivery of calcitonin by hyaluronic acid formulations. Drugs Pharma Science. 98: 1999: 563-599.

18.     Elson C, Milne A, Curran D, Kydonieus A. O-Carboxymethylchitosan as a mucoadhesive for vaginal delivery of levonorgestrel. Proc. Int. Symp. Control. Release Bioact. Mater. 27; 2000: 7201-7202.

19.     Mandal TK. Swelling-controlled release system for the vaginal delivery of miconazole. European Journal of Pharmacy. Biopharm. 50; 2000: 337-43.

20.     Patel LG. Propanolol concentration in plasma after insertion into the vagina. Br. Med. J. 287; 1984: 1247-1248.

21.     Jasonni VM et al. Vaginal bromocriptine in hyperprolactinemic patients and puerperal women. Acta Obstet. Gynecol. Scand. 1991: 493-95.

22.     Dezarnaulds G, Fraser IS. Vaginal ring delivery of hormone replacement therapy - a review. Expert Opin. Pharmacother.4; 2003: 201-212.

23.     Woolfson AD, Malcolm RK, Gallagher R. Drug delivery by the intravaginal route. Crit. Rev. Ther. Drug Carrent System. 17; 2000: 509-555.

24.     Acaturk F, Robinson JR. Effect of the spermicide, nonoxynol 9 on vaginal permeability in normal and ovariectomized rabbits. Pharm. Res. 13; 1996; 950-951.

25.     Martin A. Coarse Dispersions In Physical Pharmacy. B.I. Waverly Pvt. Ltd., New Delhi.1994; 4 th ed. pp. 495 – 496.

26.     Acosta E et al. Induced electric birefringence and viscosity studies in microemulsions, Colloids Surfaces A: Physicochem. Eng. Aspects. 106; 1996: 11–21.

27.     Regev O et al. A study of the microstructure of a four-component nonionic microemulsion by cryo- TEM, NMR, SAXS and SANS, Langmuir. 12; 1996: 668–674.

28.     Kahlweit M et al. How to study microemulsions, J. Colloid Interface Sci.118; 1987: 436–453.

29.     Bolzinger MA et al. Characterisation of a sucrose ester microemulsion by freeze fracture electron micrograph and small angle neutron scattering experiments, Langmuir. 15; 1999: 2307–2315.

30.     Auvray L et al. Evidence for zero mean curvature microemulsions, J. Phys. Chem. 88; 1984: 4586–4589.

31.     Giustini M et al. Microstructure and dynamics of the water-in-oil CTAB/n-pentanol/n-hexane/water microemulsion: spectroscopic and conductivity study, J. Phys. Chem. 100; 1996: 3190– 3198.

32.     Schurtenberger P et al. Structure and phase behaviour of lecithin-based microemulsions: a study of chain length dependence, J. Colloid Interface Sci. 156; 1993: 43–51.

33.     Yu ZJ, Neuman RD. Reversed micellar solution-to-bicontinuous microemulsion transition in sodium bis(2-ethylhexyl) phosphate/n-heptane/water system, Langmuir. 11; 1995: 1081– 1086.

34.     Ruth HS et al. Phase studies and particle size analysis of oil- in-water phospholipid microemulsions, Int. J. Pharm. 116; 1995: 253– 261.

35.     Shioi A, Harada M, Tanabe M. Static light scattering from oil-rich microemulsions containing polydispersed cylindrical aggregates in sodium bis(2-ethylhexyl) phosphate system, J. Phys. Chem. 99; 1995: 4750–4756.

36.     Shinoda K et al. Lecithin- based microemulsions: phase behaviour and microstructure, J. Phys. Chem. 95; 1991: 989–993.

37.     Corswant CV, Engstrom S, Soderman O. Microemulsions based on soybean phosphatidylcholine and triglycerides. Phase behaviour and microstructure, Langmuir. 13; 1997: 5061–5070.

38.     Corswant CV, Soderman O. Effect of adding isopropyl myristate to microemulsions based on soybean phosphatidylcholine and triglycerides, Langmuir. 14; 1998: 3506– 3511.

39.     Corswant CV, Olsson C, Soderman O. Microemulsions based on soyabean phosphatidylcholine and isopropyl myristate — effect of addition of hydrophilic surfactants, Langmuir. 14; 1998: 6864–6870.

40.     Vyas SP, Khar RK. Submicron emulsions in targeted and controlled drug delivery, Novel Carrier Systems; CBS Publishers and Distributors, New Delhi. 2002: 282 – 302.

41.     Mehta SK, Kavaljit XX, Bala K. Phase behaviour, structural effects, volumetric and transport properties in nonaqueous microemulsions, Phys. Rev. E-59; 1999: 4317– 4325.

42.     Angelico R et al. Water diffusion and head group mobility in polymer-like reverse micelles: evidence of a sphere-to-rod-to- sphere transition, J. Phys. Chem. B-102; 1998: 2883–2889.

43.     Bellare JR, Haridas MM. Characterization of microemulsions using Fast Freeze – Fracture and Cryo-Electron Microscopy. In Handbook of Microemulsion, Science and Technology. Kumar P, Mittal KL; Marcel Dekker, Inc., New York. 1999; pp. 411-523.

44.     Paul BK, Moulik SP. Uses and Applications of Microemulsions. Current Science. 80 (8); 2001: 990 – 1001.

 

 

Received on 12.04.2012       Modified on 28.04.2012

Accepted on 20.05.2012      © RJPT All right reserved