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The aim of this thesis is to review the work that has been conducted over the previous years with specific types of micellar structures for the formulation of suitable pharmaceutical containers i.e. microemulsions. Microemulsions are optimal vehicles for drug delivery because they are easy to formulate, they are thermodynamically stable and have optimal solubilization properties. Until now these superior preparations are a universally acceptable mean of delivery for parenteral, percutaneous oral and ocular route and all the reports agree to the result that there is improved bioavailability for the majority of compounds
The focus of this thesis is to review the application of microemulsions and show their importance as the most appropriate vehicle for transdermal drug delivery.
The various methods which help to the description and characterization of these systems will be discussed. Various examples will be given but mainly we will focus on the most appropriate transdermal microemulsion formulations which are analgesic drugs and anesthetic agents. Finally we will discuss the in vivo and in vitro identification methods for microemulsion stability and efficacy and also the future of microemulsion preparations
2.AIMS OF WORK
The aim of this thesis is to:
1. Present the advantages of microemulsion preparations
2. Analyze the way that there are prepared
3. Evaluate their advantages and shortcoming over commercial preparations.
4. Show that microemulsions are the future in transdermal application of various drugs
3.DEFINITION AND STRUCTURE
The term microemulsion has been introduced in 1943 by Hoar and Schulman and was defined as a clear solution obtained by titrating an oil-in-water emulsion with an alcohol(1) Microemulsions consists of water and oil and are stabilized in the presence of a surfactant and if required a co-surfactant. This process gives them their main properties which defines them as thermodynamically stable colloidal dispersions. In the case of difficult formulation of microemulsions we use a cosurfactand thus lowering the terfacial tension by three to four orders of magnitude(2). The exact definition of microemulsions is a composition of H2O an oily phase and contain amphiphile molecules and are a single phase and are thermodynamically stable in a form of an isotropic solution(3)
Property Emulsions Microemulsions
Droplet size Typically 0.2-10Î¼m <150nm
Appearance Cloudy Clear or transparent
Preparation Requires energy input Spontaneous formation
Scale up Complex Straightforward
Stability Kinetically stable Thermodynamically stable
Interfacial energy High Very low
Table 1:Comparison of emulsions and microemulsions
The differences between emulsions and microemulsions, which despite their similar nomenclature are very different, are highlighted in table 1 .
There is a large variety in the range of composition for microemulsions and their structure vary from agglomerates to spherical droplets mainly depending on the surfactant choice of nature and the composition of the microemulsions. There have been many studies suggesting that that microemulsions are 'oil in water' or 'water in oil' droplets of spherical size but later it was suggested that the main properties may be retained in the form of cubic structures
Microemulsions depending on the ratio of oil and water may be:
â€¢ Continuous water solution with dispersed oil droplets
â€¢ Continuous oil solution formulated by water in addition with inverted micelles
â€¢ Continuous (In the case of similar amounts of water and oil)
â€¢ Middle phase(Microemulsion in the middle, upper layer of oil and lower level of water)
The term microemulsion therefore may be given to a wide variety of preparations ranging from droplet type micellar structures to more complex lamellar structures(4)
4.PROPERTIES OF MICROEMULSIONS
One of the main differences between emulsions and microemulsions is that the later are much more stable. This means that the main characteristic which is droplet size has is the ability to remain unchanged over a large period of time thus promoting self emulsification of the system hence there is no significant energy input required neither the use of complex equipment is involves and we have uniform drug distribution in the formulation with the minimal resourced possible.
In order to have spontaneous formulation of a dispersion Î”G(free energy of mixing) should be negative meaning the energy of the individual components in total but unmixed is higher than the energy mixed
Î”G = Î³Î”A - T Î” S
1. Î³:Surface tension
2. Î” A:change in interfacial area on emulsification
3. Î”S: change in entropy of the system
In order for a dispersion to be Î”G , must show a minimum value. Studies have concluded that in order for microemulsion to form they depend on the free energy resulting from the low interfacial tension between oil and water ( -10 -2 -10 -3 mN/m) 
Microemulsion formation may be depended mainly on the ability of the various surfactants to decrease surface tension. In practice though this is not ideal and many times we require the presence of a cosurfactant in order to get the acceptable low surface energy. If a cosurfactand is not present , CMC(critical micelle concentration) limits the interfacial tension. The use of a cosurfactant reduces both CMC and interfacial tension (6).
High fluidity is a main disadvantage in a transdermal application. Thickening agents such as carbopol, Aerosil, Gelatin and Guar based polymers may be gelled with a lipophilic substance
Oil phase of microemulsion covers a vast variety of components which may be
1. Esters(isopropyl myristate, isopropyl palmitrate, ethyl oleate)
2. Medium chain triglycerides( caprylic acid, capric acid)
3. Alcohol(octanol and decanol)
4. Termpenes(limonene, cineole, camphor and menthol)
5. Fatty acids(oleic acid with combination of other components)
The aqueous phase is typically composed of:
1. Viscosity enhancing agents
2. Buffer salts
3. Preservatives and penetration enhancers
4. Sodium chloride
Surfactants and Cosurfactants
Drug Oil phase Surfactants Membrane
Diclofenac IPP Lecithin Human skin
Ketoprofen Triglycerides Lecithin/n-butanol Human skin
Diclofenac diethylamine - Soybean lecithin Silicone membrane and human skin
Retinoic acid IPP Lecithin and capryl glucoside as surfactant andethanol as co-surfactant Silicone membranes and pig skin
Propranolol HCL Isooctane Soybean lecithin Human skin
Scopolamine and Broxaterol IPP cyclooctane Soybean lecithin Human skin
Methyl nicotinate IPP Lecithin, cholesterol Human studies
Table 2: lecithin microemulsion based formulations
One major factor when using surfactants is their side effects on human tissue. Most non ionic surfactants are considered safe where as anionic surfactants are causing irritation and cationic surfactants are equally irritating but even more cytotoxic than anionic surfactants
Nonionic surfactant formulations are:
1. Plurol Isostearique _ (isostearic acid ester of polyglycerol, containing 30-35% of diglycerol, 20-25% of triglycerol, 15-20% of tetraglycerol, and 10% of pentaglycerol and higher oligomers)
2. Transcutol P (diethylene glycol monoethyl ether) is proposed as less irritant alternatives to the medium chain alcohols
3. Labrasol (consists of 30% glycerides-mono,di and tri- of c8 and c10 fatty acids, 50% of mono- and diesters of poly(ethylene glycol)] has also been used in microemulsions designed for topical delivery because it is nonirritant as well as capable of forming microemulsions with nonalcoholic cosurfactants [ 10] .
Toxicity aspects will be discussed in detail in a later chapter of this thesis
6.MECHANISMS OF PERCUTANEOUS ENCHANCEMENT
While the exact mechanism in which the microemulsions permeate the skin is not totally understood we know from their complex composition that several factors are involved as shown on the figure 1
Fugure 1: Mechanisms by which microemulsion components enchance drug permeation
Microemulsions may enhance transdermal drug delivery primarily by the following effects:
1. Exhibition of high solubilization capacity for the drug therefore more drug is 'in' the microemulsion and thus the concentration of the drug that reaches the skin is increased
2. The so called 'reservoir effect' which described the process by which the internal phase of the microemulsion continuously provides drug to the external phase which comes into contact with the skin and so the external phase remains saturated with the drug for a longer period of time
3. Formulation components such as surfactants, cosurfactants and oils act as permeation enhancers by increasing drug diffusion on the skin area
4. Adding various chemical enhancers to the microemulsion formulation lead to the improvement of transdermal delivery of the formulation
5. The suitable surface contact required for a successful formulation between the membrane and the vehicle is ensured by the very low interfacial tension required by all microemulsion formulations
7.CHARACTERIZATION OF MICROEMULSIONS
Even though they are very easy to produce, characterization of microemulsions is not so. The wide variety of structure is the main problem when attempting to characterize them so they are divided in some categories depending on their properties, the factors affecting drug release, stability and structure. In order to evaluate all these properties and characterize a certain microemulsion formulation we may use several techniques including NMR spectroscopy, electrical conductivity, self diffusion measurements and fluorescence spectroscopy
Figure 2: Effect of surfactant : cosurfactant ratio of the microemulsion formation region
Phase diagrams show the limits of the different phases as a function of the component composition. These diagrams are constructed after careful visual inspection of the microemulsion often by polarized light microscopy but this most often happens in the case of known composition. If required we can also map several different parameters such as conductivity, viscosity etc.
The construction of these diagrams involves a lengthy process in which the various physical parameters of the microemulsion are measures. Pre-determined ratios of surfactant mixture and oil are blended and titrated with the aqueous phase. After carefully altering the ratios by increasing or decreasing the aqueous phase the various proportions of each component are calculated and noted. Those proportions in which a microemulsion is stably formed are used to plot a pseudo-ternary phase diagram as shown on figure 2.
Transmission electron microscopy has been the most successful in the study and characterization of microemulsions  .
The main issue with T.E.M is the sensitivity of various microemulsion to heat and also the potentially introduction of exogenous materials in the form of artifacts(dust, etc). Another issue is the chemical reactions that may be caused from the introduction of electron from the microscope which may alter the structure of the microemulsion and finally the non view of contrast between the microemulsion structure and it's environment
7.2.Laser Light and Non-Optical Scattering Techniques
In the last few year laser scattering techniques(static and dynamic) and non-optical methods(X-ray scattering and SANS) are used for the characterization of the size of the colloidal phase. These techniques do not come without their disadvantages though. It has been reported that that there may be a misinterpretation of the diffusion coefficient and therefore the droplet size
A slightly different technique called the neutron scattering technique is used to to investigate the structural properties of a microemulsion
Self discussion can be defined as a random movement of a molecule made in the absence of any concentration gradient and the effect this movement has on the environment in which the molecule is localized.
In the case of microemulsion we have molecules confined in a close aggregate such as micelles and therefore we expect and find out that they have a self diffusion value 2 to 3 times lower than a pure solvent. Therefore in w/o microemulsions the self diffusion of water is slow and the self diffusion of oil is fast. The exact opposite are the results of water and oil molecules in o/w microemulsions
The highest self-diffusion coefficient are exhibited by oil and water in bicontinuous structures. Various microemulsions can be characterized based on the self diffusion value. This value is normally obtained by Proton Fourier Transform Pulse-Gradient Spin Echo NMR (PGSE NMR)
7.4.Conductivity and Viscosity
Classical rheology methods and conductivity measurements are used to define the type of microemulsion . Viscosity measurement show how drug release may be influenced by colloidal structures. A colloidal structure may be a vesicle with multilamellar layer or rod-like and worm-like reverse micelles. Usually watery microemulsions have high conductivity values whereas oily systems have low or non existence conductivity
Fluorescence spectroscopy is used to measure how easy the molecules of the fluorescent probe move in the microemulsion. This process is controlled by diffusion which varies depending on the viscosity of the medium and the microemulsion type. In water continuous microemulsions though due to slow diffusion of the water insoluble fluorescent(e.g. pyrene) the propagation of excitation is inhibited. On the contrary oil continuous microemulsions are not affected
8.TOPICALAPPLICATION OF MICROEMULSIONS
Transdermal administration of drugs has many advantages over other routes of administration especially over oral administration. It's main advantage is that it avoids systemic side effects. One disadvantage is that we get lower drug efficacy due to the transdermal penetration rate and this limits by much the amount of drugs that may be used by this route. The problem with the drug permeation occurs mainly in stratum corneum which is the outermost layer of the skin. The main use of the stratum corneum is to prevent the body from dehydrating but in this case prevent the absorption of the water based microemulsions
The main structural characteristics of the stratum corneum which is lipids seem to be essential for this function but recent findings by Engblom and Engstr6m , showed that Azone which is a well known enhancer of penetration properties increased the passing rate of water in lipid systems such as the stratum corneum
If we consider that microemulsions have a great solubilising capacity we can expect that this particular property can affect the stratum corneum assembly with consequences for drug penetration. Several studies have shown that we get penetration enhancement when using a microemulsion:
â€¢ Azelaic acid(a bioactive substance used to treat skin disorders) was found that an O/W microemulsion formed by water-propylene glycol, decanol-dodecanol, Tween 20, 1-butanol, and Carbopol 934 gave significantly better penetration than the corresponding water- propylene glycol- Carbopol "gel" (Fig. 3)
Figure 3: Azelaic acid absorption over time curve
â€¢ Tetrachyline hydrochloride
In an experiment made to understand the ability of tetracycline hydrochloride to pass transdermally into the body and was found that a microemulsion preparation composed of dodecane decanol, H2O and other surfactants resulted that the drug permeation was much more improved compared to the convential methods of preparation
Similarly, transdermally added drugs can have increased bioavailability by skipping the first pass effect on the liver allowing more drug to reach systemic circulation and thus increasing the bioavailability of the drug on site. Lecithin based microemulsion formulations of propranolol,scopolamine and broxaterol have been scientifically proven to be more bioavailable than similarly concentrated preparations(fig 4)
Figure 4: Scopolamine absorption through human skin over time
There is no denying that microemulsion preparations have shown a much more improved drug delivery when compared to similarly concentrated emulsions and gels(14). The successful preparation of a microemulsion has two major parameters. First are the internal constituents of the vehicle(oil phase, surfactants, chemical enhancers) and the second is the composition of the internal structure. Depending on the various parameters of the composition the drug diffusion on the vehicles may be altered(15,16)
There have been many studies which have proved the effect of microemulsion preparations in dermal and transdermal application and have also analyzed the various mechanisms with which microemulsions have an improved drug transport. Poor skin permeation is the main factor which affects A.I drugs and anesthetic agents due to the fact that both of these preparations require a fast onset of action
9.TRANSDERMAL APPLICATION OF ANTI-INFLAMATORY DRUGS
9.1.In vitro Studies
Due to the various problems occurring with the oral and rectal administration of drugs mainly due to the hypersensitivity of the patients G.I.T, transdermal application of these drugs have been one of the most early to be examined. The fast onset of action required from those drugs have lead to the use of specific microemulsions in order to speed up tha process of passing the outer layers of the skin and thus improving the speed of delivery and bioavailability of NSAIDs
Various microemulsions prepared with oleic acid and water for the delivery of ketoprofen showed that the drug preparation was more successful when the water in the mixture was increased to 60%[from about 5%] and the surfactant was decreased to about 28%[from 82%]. Various lipophilic drugs have also shown similar behavior. This shows that the thermodynamic activity of the drug is disproportional to the drug solubility of the drug present in the external phase(i.e. the lower the solubility the higher the thermodynamic activity). This is even more obvious when the external phase is much higher than the other various constituents in the microemulsion preparation.
Similar essays show that microemulsions prepared with lecithin have an increased in vitro drug release(17). Using as a primary material lecithin and water the prepared microemulsion has a different behavior. For example the release of diclofenac was much faster whereas the drug release was lower with the use of phospholipids due to the increased viscosity
Regarding human skin permeation we have clinical results which suggest that microemulsion preparations have higher bioavailability that aqueous preparations of diclofenac. Phospholipid preparations showed no enhancement as gels or other formulation even though they interact with the cutaneous membrane. Experimental studies like differential scanning calorimetry, and electron microscopy showed that phospholipids have an affect only when there are used as microemulsions
9.2.In vivo Studies
There are limited reports of in vivo studies in the present regarding the effects of microemulsion preparations of non steroidal anti-inflammatory drugs and their pharmacokinetic and pharmacological parameters when they are applied transdermally(18)
A recent study has show that a diclofenac preparation was 8 times more bioavailably active when used as microemulsion rather than been used as a gel preparation. Both times the drug was administered subcutaneously. In the microemulsion form the drug was subtle for about 7 hours at 0.8g/ml.
Cox-2 inhibitors like celecoxib were also evaluated in-vivo in order to understand the effect of a microemulsion preparation over a simple preparation. The results showed that the microemulsion preparation had a faster and more higher anti inflammatory effect. The experimental issues were present though since even though the higher and faster effect of the drug was correlated with the droplet size of the preparation in some cases the results were better in larger droplet sizes for some drugs and with lower droplet size in other drugs(e.g rofecoxib)
10. TRANSDERMAL APPLICATION OF LOCAL ANAESTHETICS
10.1.In vitro Studies
A previous study made on rats has shown that when we prepare a microemulsion with a cosurfactant(tetraglycol) we can have an 2 fold increase in the drug permeability in the skin over the simple preparations(e.g. gels). Of course some other constituents had to be used in the microemulsion such as glyceryl oleate and some fatty acid derivatives. These results have been confirmed by various other studies like the one made by Kreilgaard et al(20) who in his experiment used a microemulsion which had as a cosurfactant Labrasol and noticed and an increase in the flux of lidocaine across the skin by 1.5 times
Other studies in human skin have shown positive results when using microemulsion preparations over the simple gel preparations. These studies have shown that either by increase skin permeation of the drug or by increased drug deposition on the skin the resulting amount of drug that reached systemic circulation was much higher
1. Estribano et al: 1.5 times increase in drug permeation using a microemulsion composed of water and amethocaine(21)
2. Lee et al: Shown a 35% increase of lidocaine flux of oil in water microemulsion over a water in oil microemulsion across the human skin(22). This result was helpful to identify that w/o microemulsions are more appropriate for skin transport due to the increased drug partitioning at the site of action. For this preparation various chemical enhancer may be requires as in the case of the specific experiment were N-methyl pyrrolidone was used
10.2.In vivo Studies
In vitro studies were the first step into identifying the importance of drug deposition in the skin. Using different time intervals Sintov and Sapiro managed to identify the various levels of lidocaine concentration in the skin. This experiment was made in vivo using rats and the time intervals were 10. 30 and 60 minutes(23)
As expected drug localization was much higher in the upper and lower section of the rat skin comparing to the up to date most clinically used preparation. In this experiment Sintov and Sapiro used the same microemulsion but in two different forms. The first was a microemulsion in a liquid form and the second was a microemulsion of lidocaine in a patch form. Drug concentrations in the epidermis were the same for both preparations but application of the preparation in dermis showed that the patch had almost twice as much drug concentration carried through mainly due to its adhesive properties
Kreilgaard et al. performed an experiment with the aim to measure the absorption rate of prilocaine and lidocaine using once again rats(24). The results showed an amazing eight times more absorption of the microemulsion preparation over the currently used preparations and also the lag times where minimal in comparison. This result proved without any doubt the advantage of a microemulsion preparation over a non microemulsion one due mainly to the ability of the drug to move more freely in this preparation and thus influencing the delivery time
Despite many studies made in vivo and the fact that the drug delivery rate is increased when using a microemulsion preparation along with the higher amount of drug raching the site of action causing a faster and more potent analgesic effect the pharmacological effects have not been evaluated
A recent study for example was made using a lidocaine microemulsion in 10 volunteers and the results where compared to a commercial emulsion. The absorption was increased 3 fold and the lag time was much shorter(25). In the same study using the microemulsion preparation, the commercial emulsion and a placebo drug even though the results of the absorption and lag where in accordance with the first part of the test(higher absorption and lower lag) the analgesic effect on the patients was the same
Various in vivo studies of tetracaine hydrochloride, amethocaine and pentacaine have been conducted in animal testing have concluded to the result that microemulsion preparation had a faster onset of action and the analgesic effect was much faster
11.MICOREMULSION PREPARATIONS OF INDOMETHACIN AND DICLOPHENAC
Zabka et al.(26) experimented on the preparation and application of microemulsion forms of diclofenac indomethacin and pentacaine using rats. The aim of this experiment was to analyze the positive effect of a microemulsion preparation of gels versus water microemulsion preparations and commercial preparations.
The materials used were diclofenac diethyl amine. Voltaren emulgel. Indomethacin. Indobene gel H pentacaine hydrochloride and isopropyl myristate. The surfactant used was glyceryl oleate.
The two microemulsion preparations were one liquid which was composed of 25% surfactant,105 isopropyl myristate and 65% water. The second being a gel preparation contained 45%surfactant, 30%isopropyl myristate and 25% water. These two preparations were developed with the aim of achieving minimal lag time and also adequate flux across the skin and this was achieved with the use of various chemical enhancers
The first rheological measurements showed that the liquid microemulsion showed ideal Newtonian behavior(i.e. ideally viscous) whereas the microemulsion gel showed non Newtonian behavior which makes it more suitable for formulation and application
Figure 5: Flow curve of liquid microemulsion
Figure 6: Flow curve of the microemulsion gel
Indomethacin was not capable into forming a water emulsion due to the low solubilization capability whereas a microemulsion gel was formed stably with 1%quantity of indomethacin. As we can see from figure seven the microemulsion preparation of indomethacin permeated rat skin faster than indobene gel. The difference is not that obvious due to chemical nature of indobene but nevertheless indobene with chemical enhancers was lees penetrating that the microemulsion formulation.
Figure 7: Permeation of indomethacin microemulsion Vs indobene gel
Diclofenac microemulsions were able to be produced in both liquid and gel forms. As we can see from figure eight both microemulsion preparations permeated rat skin easier and allowed more drug to pass the membrane. After 23 hours microemulsion gel permeated in 7.38%, liquid microemulsion was 6.67% and voltaren emulgel was 5.76%
Figure 8: Voltaren emulgel vs microemulsion gel(MEG-D) vs liquid microemulsion(ME-D)
Azelaic acid is a saturated dicarboxylic acid that occurs naturally in wide variety of whole grains such as rye, barley and wheat. There is also some trace amounts of azelaic acid in the human body. Even though it is an acid, it is extremely weak and it is not corrosive in nature.
Azelaic acid is an effective antibacterial. It helps to destroy and reduce the growth of bacteria. It is also effective in bringing order to disordered skin growth. It is efficient in destroying free radicals and also good at inflammation reduction. It is also known to reduce pigmentation. This is good for people who have dark skin and have melasma. It is also good at reducing scars or spots left by acne.
Azelaic acid is very effective at making the skin renew and heal itself. It is useful at reducing the formation of pimples and blackheads that can occur on the skin. It is also known to kill the bacteria that cause acne and rosacea. It can help to help the skin conditions when used as a skin cream or gel. This is usually done in a concentration of 20% azelaic acid. It is also known to be used to help and stimulate hair growth. Many products that claim to restore hair have azelaic acid in them.
Azelaic acid is non-toxic, and is well very few patients have experienced any complications. There is a possibility of azelaic acid being a skin irritant for some patients, especially in the 20% concentration. As a result it is used when prescribed by a doctor.( 27)
Gasco et al.  was able to investigate a microemulsion preparation of azelaic acid and compare it's effects over commercial gel formulations of the same concentration. Drug permeation was found to be much higher. Using also a chemical enhancer(dimethyl sulfoxide) he was able to determine that the amount of drug was successfully enhanced and it was increased 20% when the amount of the chemical was doubled
Another study consisting of 72 individuals was aiming to discuss the period of treatment and the regression of the symptoms. Two creams were created. The first had a high amount of azelaic acid(about 20%) and the second had about one third of the quantity but was prepared in a microemulsion form. The reduction of the symptoms was the same thus showing that the microemulsion preparation allowed the lower amount of drug to increase it's effect 4-fold and also being a lower amount of drug, the second preparation had a smaller period of treatment(29)
Apomorphine (Apokyn, Ixense, Spontane, Uprima) is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix. Apomorphine does not actually contain morphine or its skeleton, or bind to opioid receptors for that matter. The -apo prefix relates to it being an aporphine derivative.
Historically, apomorphine has been tried for a variety of uses including psychiatric treatment of homosexuality in the early 20th century, and more recently in treating erectile dysfunction. Currently, apomorphine is used in the treatment of Parkinson's disease. It was also successfully used in the treatment of heroin addiction, a purpose for which it was championed by the author William S. Burroughs. It is a potent emetic (i.e. it induces vomiting) and should not be administered without an antiemetic such as domperidone. The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances.
For treatment of erectile dysfunction, it is believed that dopamine receptors in the hypothalamic region of the brain are the main target, as although dopamine receptors in the penis do facilitate erection, they do so far more weakly than those in the brain(http://en.wikipedia.org/wiki/Apomorphine)
Trying to investigate the positive effect that a microemulsion preparation may have on apomorphine a test was made (32). The microemulsion was composed of isopropylmyristate decanol, octanoate and taurocholate. Apomorphine was off course the main ingredient and was used as the aqueous phase whereas the other ingredients were used as the oily phase. Drug permeation was steady in all cases. The analysis of the pharmacokinetic parameters showed that due to the steady release of the drug, and the prolonged therapeutic effects led to the conclusion that microemulsion preparations of apomorphine are the future in the add-on treatment of Parkinson(33)
Beta blockers is a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias, cardio protection after myocardial infarction (heart attack), and hypertension. As beta adrenergic receptor antagonists, they diminish the effects of epinephrine (adrenaline) and other stress hormones. Invented by Sir James W. Black in the late 1950s, propranolol was the first clinically useful beta blocker; it revolutionized the medical management of angina pectoris and is considered to be one of the most important contributions to clinical medicine and pharmacology of the 20th century. Beta blockers may also be referred to as beta-adrenergic blocking agents, beta-adrenergic antagonists, or beta antagonists.( 34)
Microemulsion formulations of beta blockers is a novel concept. The aim is to produce a more thermodynamic activity and therefore effect, resulting from the water uptake which reduces the apolar drug solubility. Different blocker were used in rabbits and the effects were much faster decreases in the rate of tachycardia
As always toxicity of a preparation is the most important aspect that has to be examined before a drug is suited capable for administration. The main issue with microemulsion is the chemicals used as surfactants and cosurfactants. For example alcohol have been known to cause a toxic effect and these are the most commonly used surfactants in microemulsions. Other types of cosurfactants with potential toxic effects are aliphatic or aromatic oils and ionic surfactants. In a recent study butanol surfactants were shown to have a dose dependant reduction in fetal weight and also had an increase in mitochondria of hepatocytes
Also examined for their toxicity are non-ionic surfactants. Despite that in large amounts they can be toxic, their good biological acceptance, and their ability to work without the use of a cosurfactant makes them suitable for a more extensive use in microemulsion formulations and especially for topical preparations. Even more acceptable than non-ionic surfactants are the phospholipids regarding their lack of toxicity
Other acceptable microemulsion preparations include phospholipid systems with the addition of cosurfactants but despite the initial promising results the use of cosurfactants in a chemical forms will always undermine the use of this system. So in order to accept phospholipids as the universal way in which microemulsion preparation will be prepared phospholipids that do not require the use of a cosurfactant to elicit their effects must be developed
Finally the latest biocompatible preparation includes a mixture of water, triglycerides and monoglycerides and due to its unique properties it is acknowledged as the most capable preparation for orally administered microemulsions(35,36,37,38)