Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: https://www.tandfonline.com/loi/iddi20

Microemulsions as Transdermal Drug Delivery

Systems for Nonsteroidal Anti-inflammatory Drugs
(NSAIDs): A Literature Review

Tarique Vicario Benbow & Jacqueline Campbell

To cite this article: Tarique Vicario Benbow & Jacqueline Campbell (2019): Microemulsions
as Transdermal Drug Delivery Systems for Nonsteroidal Anti-inflammatory Drugs
(NSAIDs): A Literature Review, Drug Development and Industrial Pharmacy, DOI:
10.1080/03639045.2019.1680996

To link to this article: https://doi.org/10.1080/03639045.2019.1680996

Accepted author version posted online: 16

Oct 2019.

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Microemulsions as Transdermal Drug Delivery
Systems for Nonsteroidal Anti-inflammatory Drugs
(NSAIDs): A Literature Review

Corresponding author: Tarique Vicario Benbow - The University of British Columbia Faculty of

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Pharmaceutical Sciences, British Columbia, Vancouver, Canada. ORCID: 0000-0001-7613-6957.
tariquebenbow@gmail.com

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Dr Jacqueline Campbell - University of the West Indies, Faculty of Medicine, Mona, Jamaica

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ORCID: 0000-0002-8757-5872

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Abstract: Pain is a global crisis and significant efforts have gone into the development of drugs that can
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be used to treat pain. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are a class of analgesics that act
to selectively relieve pain and inflammation without significantly altering consciousness. Although there
have been many advancements with NSAIDs drug development; these drugs still present with severe
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adverse effects and toxicities, which often limits their use in many patients. Moreover, others are
inadequate in relieving specific types of pain such as localized or nerve pain because of poor systemic
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absorption with conventional delivery systems. The topical route of drug delivery has been used to avoid
many of these effects, but not without challenges of its own. The skin acts as an impermeable barrier to
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most polar drug candidate and absorption across the dermal membranes is often too slow and
incomplete to produce meaningful therapeutic benefit. Nevertheless, the use of microemulsions as
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topical delivery systems for small molecule drug candidates like NSAIDs has been posited as a solution to
this problem for years. This review focuses on the recent use of microemulsions as a probable solution
to the challenges of transdermal drug delivery of NSAIDs and how microemulsions may be used to
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enhance the development of more effective but safer analgesic drug products for patients.
1.1 Introduction
Pain remains to be one of the most prevalent and severe to treat ailments in the medical field. With
advancements in the 19th and 20th centuries, researchers have identified new targets for the treatment
of pain1. These targets have been the basis for the development of novel analgesic drugs which have
frequently been used to treat pain over the last century. Non-steroidal Anti-inflammatory Drugs
(NSAIDs) constitute an important class of drugs with therapeutic applications in pain that have spanned
several centuries2. NSAIDs are usually prescribed for mild to moderate pain from osteoarthritis,
rheumatoid arthritis, inflammatory pain, musculoskeletal and dental pain2,3. They are a class of

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analgesics which, despite the high success rate in treating pain and inflammation, presents with many

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risks. Patients who regularly take oral NSAIDs like Diclofenac, Ibuprofen and Naproxen, are usually at risk

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for small-intestinal mucosal ulceration and bleeding, which may present as anaemia of undetermined
gastrointestinal origin or protein loss4. Such ulcerations often lead to more compelling pathological

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conditions such as Helicobacter pylori peptic ulcer disease2. These diseases may prove challenging to
treat, which adds additional medical expense and ultimately may result in a decreased quality of life for
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patients taking these drug products.
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The topical route of administrations of NSAIDS has been posted as a viable option in thwarting these
challenges5,6. Transdermal administration of NSAIDs offers many advantages over conventional oral and
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invasive techniques of drug delivery7,8. Since the discovery of microemulsions by Jack H Schulman, there
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has been huge progress made in applying microemulsion systems in plethora of research and industrial
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process. Microemulsions are optically isotropic systems consisting of water, oil and amphiphile. These
systems are beneficial due to their thermodynamic stability, optical clarity, ease of preparation, higher
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diffusion and absorption rates. The favourable drug delivery properties of microemulsions appear to
mainly be attributed to the excellent solubility properties. Moreover, it has been reported that the
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ingredients of microemulsion can effectively overcome the diffusion barrier and penetrate through the
stratum corneum of the skin. The vehicles may also act as penetration enhancers depending on the
oil/surfactant constituents, which involves a risk of inducing local irritancy. This review will examine the
current use of microemulsions as transdermal drug delivery systems and position this technology as a
possible solution in overcoming the limitations of systemic NSAID use.
1.2 Pharmacology of Non-Steroidal Anti-inflammatory Drugs
Ever since the discovery of aspirin, small molecule therapeutics have been widely prescribed to treat
inflammation and pain. The arachidonic acid pathway is central to inflammatory response and
consequently is a prime target for drugs that block inflammation9. NSAIDs effect their therapeutic effect
through either competitive or non-competitive inhibition of the cyclooxygenase isoenzyme which is a
key mediator in the arachidonic-acid pathway10. In the early 1990s the second isoform of COX was
discovered, providing a novel target to develop anti-inflammatory agents with superior safety profiles
compared to traditional NSAIDs. There are two iso-forms of the enzymes COX-1 and COX-2, and the

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selectively of particular NSAIDs for each enzyme has significant implications on the both therapeutic

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application and side effect profile of the drugs. Aspirin and several small molecule NSAIDs are known to

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inhibit the enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2)11. The characteristic feature of traditional
nonselective COX inhibitor NSAIDs was the presence of a carboxylic acid (COOH) functional group. All

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nonsteroidal anti-inflammatory drugs (NSAIDs) are characterized by a high degree of protein binding and
small volumes of distribution. Differences in clearance account for the variability in half-life among these
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drugs. The majority are metabolized by the liver through a variety of pathways12. These drugs are
subject to drug interactions of several mechanisms, including protein-binding-displacement interactions,
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induction or inhibition of hepatic drug metabolism, and competition for active renal tubular secretion
with other organic acids.
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Although though the pharmacokinetics of some NSAIDs may be significantly affected by contaminant
administration of other drugs this seldom leads to serious complications13,14. Concurrent administration
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of NSAIDs with antacids and local gastroprotective drugs may delay the absorption of NSAIDs and thus
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reduce therapeutic effect15. Meanwhile other drugs such as cholestyramine may also decrease oral
absorption of many drugs including NSAIDs when taken concurrently16. Others may also decrease
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plasma concentrations of those NSAIDs that undergo enterohepatic circulation (e.g. piroxicam.
tenoxicam) by interrupting the enterohepatic cycle. Corticosteroids stimulate the clearance of salicylates
and thus reduce the Plasma concentrations of many NSAIDs17,18. The COX-2 inhibition might reduce the
risk of gastrointestinal toxicity, but several studies have shown the cardiovascular side effects of this
inhibition18,19. Mechanisms of the cardiovascular side effects are controversial yet. The clinical relevance
of many of these interactions with NSAIDs is still not well established, however one thing is certain is
that NSAIDs are effective anti-inflammatory drugs that form the mainstay of many painful and
inflammatory conditions. It therefore goes without saying that alternatives techniques might be used to
manage these pharmacodynamic and pharmacokinetic interactions.

1.3 Advantages of Transdermal Delivery of NSAIDs

Transdermal delivery aims to treat systemic conditions by penetration of drugs across the layers of the
skin and into the systemic circulation20,21. Transdermal delivery systems can transport a drug or
macromolecules painlessly through the skin into the blood circulation at a fixed rate22. Advantages of

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these systems include; prevention of hepatic first-pass metabolism, enhancement of therapeutic

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efficiency and maintenance of steady plasma level of the drug23. Drugs can penetrate the skin through

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three pathways. The transcellular route, where drug moiety passes through both keratinocytes and
lipids (straight path to the dermis)24. The Paracellular route, where the drug remains in lipid moiety

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attached to keratin; and the transappendgeal route, which provides a continuous channel for drug
permeation but is hindered easily due to the presence of hair follicles and sweat ducts 25. Since the skin
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is the largest organ in the body, transdermal delivery is also more selective and targeted delivery
method. As a result, a lower dosage of drugs is typically required in this delivery method26. Despite the
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many benefits of transdermal delivery of drugs, relatively few formulations are commercially available
due to the barrier function of stratum corneum which limits permeation of most exogenous
substances27,28. When the drug molecules penetrate via stratum corneum, they either follow the
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transcellular or intercellular route. The transcellular route, also known as the polar pathway, involves
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drug penetration through the corneocytes and the lipid lamella. The drug molecules need to penetrate
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the skin through the phospholipid membrane and the cytoplasm of the dead keratinocytes present in
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the stratum corneum. Hence, the drug molecules encounter resistance while permeating because they
have to overcome both the lipophilic and hydrophilic barriers.
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The transdermal route has been known to eliminate oral gastrointestinal (GI) adverse effects and
maintain the plasma drug level for a more extended period and is thus suitable for prolonged treatment
of chronic disease such as chronic pain29. Recent studies have shown significant drug levels in deep
tissues such as fascia, muscle, and synovium after topical application, which is a desirable feature for the
30,31
relief of local pain with a low dose, thereby reducing systemic side effects . The other advantages
associated with the topical drug delivery system with NSAIDs include the following: Patient compliance
and acceptance, Ease and convenience of application, Painless and non-invasive technique,
Improvement in drug bioavailability, Better physiological and pharmacological response, minimum
systemic toxicity and exposure of the drug to non-infectious tissue/sites32.

1.4 Challenges to Transdermal Drug Delivery of NSAIDs

Transdermal drug delivery represents a desirable and innovative mode of NSAID drug administration
across the skin, mostly owing to the possibility of achieving the systemic effect of drugs with limited side
effects6,31. However, the highly organized structure of the skin, which acts as a barrier to drug
penetration, makes this route challenging nonetheless.33 The human skin is composed of a multilayered

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structure and consists of the epidermis, dermis, and hypodermis layers33. The skin is an excellent natural

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barrier to drug absorption due in large part to the outermost layer called the stratum corneum. This

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layer is just 10–15 μm thick and comprises a brick-and-mortar structure, where the "bricks" are cell
remnants filled with cross-linked keratin and water called corneocytes, and the "mortar" is extracellular

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lipids organized mostly in bilayers. Due to the specific physical structures and chemical properties of the
stratum corneum, the skin does not allow the passive penetration of most therapeutic molecules 34,35.
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Successful conventional transdermal drugs have been a small molecule, lipophilic, and low dose, with
physicochemical requirements more stringent than those associated with Lipinski's rule of fives for oral
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draggability25. Drugs that are able to partition into and diffuse within these lipid bilayers are good
candidates for transdermal delivery36.
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There is also the issue of biological incompatibility. Most transdermal formulations require chemicals
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which can irritate the skin, are hyper-allergenic and therefore are not feasible to use in patients37,38. As a
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result, there are very few excipients which can be used for commercially accepted products35,39.
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Nevertheless, microemulsions chemical and physical enhancement methods can be used to disrupt the
stratum corneum structure on the molecular scale and thereby increase skin permeability to small drug
molecules such as NSAIDs40. Chemical enhancers have been widely used to enhance transdermal drug
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delivery by mechanisms including extraction of stratum corneum lipids (e.g., solvents like ethanol) and
disruption of lipid bilayer structure (e.g., surfactants), and are usually designed to achieve a balance
between maximizing skin permeability while minimizing skin irritation2541. The chemical structure and
physicochemical characteristics of the drug molecule are essential properties in deciding its permeability
through the skin. Its molecular weight influences the diffusivity of the drug molecule through the skin.
The drugs with a molecular weight of less than 500 Da show good permeation. This has significant
implication for the use of microemulsion as transdermal drug delivery systems for NSAIDs, as most
NSAIDs fall within the molecular weight range of 20-60 kDa42. This thus reintegrates the viability of these
systems to deliver NSAIDs from systemic use topically.

Among all the skin layers, the stratum corneum is the primary barrier for NSAID drug permeation. The
exposed layer of the skin (also termed as horny layer) is approximately 10 mm thick. It has barrier
property due to the presence of 79–90% of protein and 5–15% of lipids. The multilayered epidermis
varies in thickness which mainly depends upon cell thickness and layers of the epidermis. However,
there are some provisions for transfer of natural compound across the skin, including the intercellular,

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follicular and intracellular pathway. The intercellular path is suitable for the transmission of hydrophilic

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drug substances. The follicular or transappendgeal path provides the direct and rapid transfer of

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contents to the infundibulum region while the intracellular transport facilitates the permeation of
lipophilic drug substances. Besides the structure of the skin, the physicochemical characteristics of the

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permeant also play a vital role in its absorption. These characteristics include partition coefficient and
diffusion coefficient, which in turn are dependent on the other parameters such as molecular weight,
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size of the molecule, degree of ionization, and the physicochemical structure of the drug molecule. All
these factors are interdependent; none of them can be ignored as all of them have their influence
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toward the drug absorption.

1.5 Microemulsions to Aid Transdermal Delivery of NSAIDs

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Microemulsions were first introduced by Schulman et al. in 1943. Microemulsion possesses many uses in
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the pharmaceutical and food industry and as such, have been studied at great lengths. Microemulsions
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are transparent, stable, isotropic mixtures of oil, water, and surfactant, frequently in combination with a
cosurfactant. Microemulsions are versatile carriers with their various remarkable properties like
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enhanced bioavailability of the poorly soluble drugs, high absorption, and permeation because of very
low surface tension and small droplet size as well as a cost-effective approach43. A microemulsion is
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formed when the interfacial tension at the water/oil interface is brought to a very low level, and the
interfacial layer is kept highly flexible and fluid5,44. This condition is usually met by a careful and precise
choice of components, their respective proportions and using a cosurfactant which brings flexibility to
the water/oil interface. In contrast to ordinary emulsions or macroemulsions, microemulsions form
upon simple mixing of the components and do not require the high shear conditions generally used in
the formation of conventional emulsions45.
Macroemulsions, require high energy to produce as well as they are not thermodynamically stable and
tend to break down or exhibit phase separation (flocculation or coalesce) over time. This high energy
requirement results in high production cost, formulation development challenges and decreased shelf-
life. Considering the high solubilizing potential of microemulsions, one of the main advantages of
microemulsions in delivering NSAIDS is that other classes of pain drugs can be merged into the
formulation; therefore, the skin thermodynamic activity is improved, allowing a wide range of
concentrations from the microemulsion vehicle to the skin46. This can be adopted for delivery of non-
steroidal anti-inflammatory drugs which have poor solubility in conventional delivery vehicles47. Besides,

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drug permeation is improved by the use of microemulsions owing to the synergistic effects of

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components for enhancing drug delivery and therapeutic effect.

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1.6 Physical and Chemical Properties of Microemulsions
The individual components of the microemulsion system are also thought to play a critical role in

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increasing drug delivery across the skin48. The role of penetration enhancers played by the amphiphilic
components of the microemulsions and the internal mobility of the drug within the vehicle also
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contributes to the overall performance of microemulsions in dermal or transdermal drug delivery 22,49.
The components of the oil phase and other penetration enhancers used in microemulsion systems can
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increase the permeation of drugs themselves 30,50. These components can diffuse to the skin surface and
increase the permeation of drugs, either by disrupting the lipid structure of the stratum corneum
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(facilitating diffusion through the skin barrier) or by increasing the solubility of the drug in the skin (i.e.,
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increasing the partition coefficient of the drug between the skin and the vehicle)30. Another researcher
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evaluated the penetration of components of microemulsions; in their research, they observed that all
components disturbed the stratum corneum layer to the degree that was proportional to the level of
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the respective component present in the skin51. Also, it was suggested that the more efficient uptake
from the microemulsion might imply the possibility of mutual enhancement52. Another theory through
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which seeks to explain why microemulsion systems provide enhanced penetration and therefore
bioavailability of drugs across the stratum corneum is due to their ability to hydrate the skin32. Water is
considered a penetration enhancer for many drugs, and it is this effect that may contribute to the
formulation of penetration-enhancing properties53.

Fatty acids, esters, urea, terpene and alcohols are also commonly investigated diffusional enhancers
used in commercial products. One of the most intensely studied enhancing acids is oleic acid. It has been
proposed that oleic acid undergoes phase separation within the stratum corneum, providing pathways
of lesser resistance for the penetrating drug. Ethanol is also used as a vehicle for transdermal delivery
and enhances permeation of both hydrophobic and hydrophilic compounds. Enhancement may occur by
several mechanisms. It was suggested that ethanol in concentrations < 50% functions as an agent
fluidizing SC lipid54. The combination of ethanol with other solvents or enhancing agents may act to
increase penetration enhancement even more than ethanol alone. It is also possible to tailor a vehicle
for either a lipophilic or hydrophilic drug. Chemical enhancers could be effective only when drug skin
permeation needs a moderate degree of improvement55. However, for molecules with extremely poor
percutaneous absorption, such as large hydrophilic or ionized drugs, these enhancers will probably not

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be effective and more sophisticated technologies are needed.

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The type of microemulsion formed depends on the nature of surfactant56. Surfactant contains a

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hydrophilic head group and lipophilic tail group41. The areas of these groups, which are a measure of the

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differential tendency of water to swell head group and oil to swell the tail area, are essential for specific
formulation when estimating the surfactant HLB in a particular system. When a high concentration of
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the surfactant is used or when the surfactant is in the presence of salt, the degree of dissociation of
polar groups becomes lesser, and resulting system maybe water-in-oil type. Diluting with water may
increase dissociation and leads to an oil-in-water system. Ionic surfactants are strongly influenced by
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temperature. It mainly causes increased surfactant counter-ion dissociation. The oil component also
influences curvature by its ability to penetrate and hence swell the tail group region of the surfactant
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monolayer. Short chains oils penetrate the lipophilic group region to a great extent and result in
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increased negative curvature57. Temperature is critical in determining the effective head group size of
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non-ionic surfactants. At low temperature, they are hydrophilic and form standard o/w system. At
higher temperature, they are lipophilic and form water-in-oil systems. At an intermediate temperature,
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microemulsion coexists with excess water and oil phases and forms a bicontinuous structure.
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1.7 Mechanisms of Drug Delivery Across the Skin

Several mechanisms have been proposed to explain the penetration-enhancing effect of
microemulsions. Most likely, it is the overall combination of various mechanisms that result in the
penetration-enhancing effect, and no mechanism in isolation seems to provide a sufficient explanation
for the superiority of microemulsions compared to other systems58. Increased penetration enhancement
form microemulsion is hypothesized to be due to the increased drug loading capacity of these systems59.
Derle posits that microemulsions can deliver substantial amounts of water and topically applied agents
into the skin than water alone or other traditional vehicles such as lotions or creams40. He explains that
this is because they act as a better reservoir for a poorly soluble drug through their capacity for
enhanced solubilization40. Conversely, Thakkar investigated the enhanced transdermal delivery of
diclofenac using w/o microemulsion and the mechanistic approach of skin permeation of diclofenac
from the microemulsion27. In this study, the research used surgically removed subcutaneous tissue from
Sprague Dawley rats to assess the permeation of the drug from the microemulsion into the skin. The
study demonstrated that that microemulsion formulations showed significantly (p<0.05) higher
permeation compared to that exhibited by the oily solutions, aqueous solution, and oil–S mix

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solutions27. The researchers also found that skin permeation is influenced by changes in the

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concentration of oil phase and S-mix, changes in S-mix ratio and drug loading into the oil phase and

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aqueous droplets of w/o microemulsion27. Skin permeation mechanisms involve partition of the drug
from the oil phase, while drug from aqueous droplets permeated through the skin by carrier effect of

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the oil phase60,61. The result is a finished product that provides an increased rate of absorption of the
drug, which in turns provides increased bioavailability of the drug and thus a more significant
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therapeutic response when compared with conventional gels or macroemulsion formulations60.
Microemulsion reduces the interfacial tension at the skin surface and solubilizes the drug. The
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permeation enhancer sometime surfactant or lipid, used in the formulation may dissolve or perturbates
the lipid bilayer structure of the stratum corneum62,63. By this way, it minimizes the barrier function of
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the stratum corneum and opens a pore or passage for drug transfer across the skin. The reservoir effect
of the internal phase maintains a constant driving force of drug from the external phase to the skin and
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prolongs absorption. Since the diffusion of the drug into the skin only occurs from the external phase of
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the microemulsion, the internal phase continually supplies the drug to the external phase so that it
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remains saturated with the drug.

1.8 Effect of Microemulsion Components on various NSAID microemulsion formulations

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The transdermal drug delivery potential of microemulsions is dependent not only on the applied
constituents of the vehicle but also drastically on the composition/internal structure of the phases which
may promote or hamper the drug distribution in the vehicles. Ketorolac tromethamine (KT) is described
as a non-steroidal anti-inflammatory drug (NSAID). Among various NSAIDs, ketorolac tromethamine is
commonly used for post-operative and emergency relief of pain. A study conducted to observe the
effects of microemulsion excipients on ketorolac absorption across the skin showed that the oil, S/C
mixture, and water contents in microemulsion formulations affect physicochemical characteristics and
permeation parameters of the drug64. The best combinations for ketorolac microemulsion preparations
included isopropyl myristate (oil phase), Tween 80-Labrasol (surfactant mixture), and Pleurol oleic-
PEG400 (cosurfactant mixture)64. The water phase, surfactant-cosurfactant (S/C) mixture, and the oil
phase can be synergistically mixed to improve the flux of drugs. An increase in water and oil phase
percentage and reduction in S/C ratio caused an increase in Jss parameter in ketorolac microemulsion
formulations.

Another study that investigated the use of microemulsion formulation to increase the permeability of
diclofenac sodium across dermal layers also support the notion that the choice of microemulsion

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components can influence permeation rate. In this study, microemulsion was prepared using

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caprylocaproyl polyoxyl-8 glycerides, diethylene glycol monoethyl ether, and propylene glycol

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monolaurate. For enhancing the viscosity, carbopol was used to form a microemulsion-based gel.
Formulations with enhanced viscosity demonstrated a statistically significant increase in both release of

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the drug 76.67% after 6 hours compared to the control 69.28%65. Furthermore, increased viscosity
increases the acceptability of the formulations in patients, which might improve compliance once the
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technology is translated into clinics65. Similarly, others have investigated the potential of microemulsion
formulations for transdermal delivery of indomethacin (IND). Microemulsion formulations with different
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surfactant: cosurfactant ratios (Smix); were prepared by the spontaneous emulsification66. A significant
increase in the steady-state flux (Jss), permeability coefficient (Kp), and enhancement ratio (Er) was
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observed in microemulsion formulations compared with the conventional IND gel. Interestingly these
microemulsion formulations were tested in carrageenan-induced paw oedema in rats, an in vivo model
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of inflammation. All formulations exhibited anti-inflammatory activity significantly higher than that in
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the IND gel group (P<0.05 and P<0.001)66. The anti-inflammatory effects of microemulsion formulations
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showed a significant increase in percent oedema inhibition value after 4 hours66.

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Lornoxicam another NSAID has been formulated into a microemulsion hydrogel for topical delivery. A
microemulsion using Tween 80, ethanol and Carbopol 934p, HPMC K-15M and Xanthan gum was
selected as surfactant, co-surfactant and hydrogel thickening agent respectively67. A higher
concentration of surfactant results in finer droplet size; however, it also resulted in corresponding
increasing viscosity of the formulation and zeta potential value lies between -21.4 to -8.1. The results
showed that the content of microemulsion based hydrogels components (oil, Smix and water) had a
significant effect on their physical, rheological and in vitro drug release characteristics67. This provided
evidence that lornoxicam hydrogel can be used as an anti-inflammatory and analgesic agent for topical
drug delivery. Another important strategy was adapted by Ali and co-workers (2017), they prepared a
microemulsion based reservoir type transdermal patch for the topical delivery of an anti-inflammatory
agent, dexibuprofen. The microemulsion was prepared by using ethyl oleate (oil phase) and Smix, tween
80 and propylene glycol (2:1) with the help of a phase diagram68. In vitro release studies of the
formulations showed 79.73% release of drug in 24 h and followed zero-order release kinetic which was
best described by Korsmeyer-Peppas model68. The in vitro permeability study shows a significant
increase in the skin permeability; the cumulative drug permeation was observed as 8174.45 μg/cm268.
By these properties, the selected microemulsion was incorporated into the transdermal patch. The skin

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sensitivity assay confirms the safety of the patch. Afterwards, the in vivo anti-inflammatory study on the

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hind paw rat model demonstrated a significant reduction in the inflammation and swelling68. Overall,

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this study suggested the prepared formulation as a promising strategy for skin drug delivery.

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Zaltoprofen is a propionic acid derivative, belongs to the new generation NSAID and potentially used in
the treatment of spondylitis, rheumatoid and osteoarthritis, post-operative pain and respiratory tract
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infection69. However, its oral administration experience severe gastrointestinal side effects, including
gastric ulcer and bleeding18,42. Also, the frequent dosing of the drug was needed due to the shorter half-
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life (2.8 h) of the drug70. Thus, to reduce the side effect and improve the therapeutic efficacy of the drug
Mishra et al. (2016) developed a transdermal microemulsion and microemulsion based gel using Capryol
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90 (oil phase), Cremophore® RH 40 (surfactant) and Transcutol® P (co-surfactant). Further, the gel was
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prepared by adding Poloxamer 407 to the microemulsion formulation. The drug content of the
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microemulsion based gel was observed 99.22%, which reflects the better drug loading ability of the
formulation69. The microemulsion formulations formed also impacted product physical appearance and
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usability. The spreadability, extrudability, and viscosity of the microemulsion based gel were found to be
31.68 g.cm/s, 83.6%, and 40.12 Pa.s, respectively71. The in vitro and ex-vivo release and permeation
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studies shows around 84.8% and 81.7% drug release in 12 h respectively, which was higher than the
conventional formulation69. The microemulsion based gel releases the drug in a prolonged and sustained
manner. Moreover, the kinetic release study shows the drug releases under the non-Fickian mechanism
and follows the zero-order release kinetics. The in vivo anti-inflammatory was analyzed on carrageenan-
induced paw oedema rat demonstrates a significant reduction in the inflammation and oedema.
Additionally, the analgesic activity shows improvement in the analgesic effect of the drug when loaded
in the microemulsion formulation. At the same time, the skin irritation test and dermal
toxicity assessment show the non-irritability and safety of the formulation. Hence, the formulation is
proved as a potential carrier system for topical administration of the NSAID71.

1.9 Future Directions

The discovery of microemulsion has raised many ideas as to how these systems can augment current
medicinal treatments. Further work can investigate the possibility of using microemulsion in conjunction
with nanotechnology to increase the prospects of targeted drug delivery. Targeted drug delivery is a
novel approach to drug delivery, which involves using mechanisms which allow for direct presentation
and target of drugs at the point of action. The use of microemulsion may provide some benefit in

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allowing for increased absorption with these systems; however, more work would be needed to conduct
to test these claims72. Additionally, microemulsion systems can be further explored in the delivery of

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oral drugs which prove challenging to formulate in oral dosage forms because of reasons such as; poor
solubility, unpleasant tastes (masking effect) and stability in the gastrointestinal tract. Finally, future

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work can be pursued to investigate and compare the number of drugs transported across the skin with
microemulsion formulations and current topical dosage forms to further prove or disprove their
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superiority as transdermal drug delivery systems.
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2. V. Figueiredo, C. P. R. Ibuprofen Nanoparticles for Oral Delivery: Proof of Concept. J.
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3. Derry S, C. P. D. S. J. A. P. W. P. J. & Moore, R. A. Topical NSAIDs for chronic musculoskeletal pain
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4. Baraf, H. S. B., Gold, M. S., Petruschke, R. A. & Wieman, M. S. Tolerability of Topical Diclofenac
Sodium 1% Gel for Osteoarthritis in Seniors and Patients With Comorbidities. Am. J. Geriatr.
Pharmacother. 10, 47–60 (2012).
5. Benbow, T. & Campbell, J. Comparison of the Topical Analgesic Effects of a Novel Diclofenac
Microemulsion to a Marketed Diclofenac Macroemulsion Formulation in Rats Using the Tail Flick

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