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Transdermal Drug Delivery has been around for many decades and presents many advantages over other routes of administration such as oral and parenteral. Over the years there has been an increasing interest in Transdermal drug delivery and methods to allow incorporation of larger drug molecules. First generation Transdermal drug delivery were the first designs of Transdermal patches introduced in to the market which used the reservoir and matrix systems. Second and third generation Transdermal designs concentrate on these designs however have been enhanced to allow better penetration through the skin and allow administration of other drugs such as proteins and vaccines.
In the past three decades delivery of drugs via the skin has become increasingly popular. Topical preparations such as ointments and creams are used for local treatment of dermal conditions such as psoriasis and eczema. When applied to the skin these preparations deliver the drug within the formulation to the tissue it is in contact with (Ghosh, 1997) and hence is used for local drug delivery. These preparations presented many advantages and disadvantages, one of the disadvantages being systemic absorbance, which was first noted with the use of dimethylsufoxide and nitroglycerine during world war II and was seen as an advantage for future drug development consequently leading to the development of nitroglycerine ointment to reduce the risk of angina in the 1950s (El-Kattan, 2000). Pharmaceutical companies quickly caught on to the idea of systemic drug delivery and in 1981 the first Transdermal patch for morning sickness was introduced into the pharmaceutical market by Alza Corporation (Thomas, 2004).
Figure 1: Basic layout of a transdermal patch (Sircus, 2008)
http://www.thenhf.com/article.php?id=579Transdermal dosage forms are formulations that are applied to the skin for systemic absorption. It enables administration of specific quantities of a drug by a patient for a long duration of time. They are usually in the form of patches which allows delivery of a drug at controlled rates. A transdermal patch is a medicated patch which is approximately less than 40cm2 in size (Ghosh, 1997). The basic structure of a patch (fig 1) comprises of a clear backing which is impermeable to any external matter such as moisture, a drug reservoir which contains the active pharmaceutical ingredient (API), a drug release membrane which facilitates the release of the API from the patch and a contact adhesive to allow the patch to stick to the skin. http://htmlimg1.scribdassets.com/abm497v9knyqirk/images/3-4fa37c99a5/000.jpg
Currently in the pharmaceutical market there are more than 19 formulations available for administration (table 1), most common being patches for nicotine cessation and fenatyl and also for analgesic purposes (Prausnitz, 2008).
Nicoderm, Habitrol, ProStep
GlaxoSmith Kline, Novartis, Elan
Post Hepatic Neuralgia Pain
Acute Postoperative Pain
Major Depressive Disorder
Table 1: Some Examples of Food and Drug Administration (FDA) approved Transdermal Products from 1979 to 2007 within the USA.
This review will be focusing on the three generations transdermal drug delivery (TDD), and future potential with respect to these formulations.
3. Advantages and Disadvantages of Transdermal Drug Delivery
Oral dosage forms are the leading route of drug administration within the pharmaceutical market, however the major downfall of such formulation is that many drugs are prematurely metabolised via the liver upon administration or degraded by enzymes present within the gastrointestinal (GI) tract. For this reason the dose administered to a patient is high, so are the side effects exhibited and compliance within patients is consequently reduced. Parenterals such as intravenous injections are also seen as an alternative for problem patients such as in geriatric patients however this is accompanied by pain and risk factors such as infections due to the needle.
Transdermal formulations on the other hand aid in increasing compliance within patients as they firstly eliminate the fear of swallowing associated with tablets and capsules and eliminate fear associated with parenterals. They furthermore allow drugs to be absorbed into systemic circulation without first pass elimination or having to encounter any enzymes within the GI tract hence decreasing the quantity of drug required to be administered, consequently decreasing side effects exhibited. As well as eliminating issues associated with other formulations transdermals are designed to allow drug release over a period of time hence resulting in constant drug plasma concentration and decreasing the dosing interval and presenting a longer time of action (Prausnitz, 2008 and Ghosh, 1997). In terms of manufacturing transdermal formulations are also cheaper to manufacture compared to other dosage forms such as parenterals.
Like all formulations transdermal drug delivery also possesses many disadvantages, one being the inability of incorporate large amount of drug within the formulation. Only drugs with molecular masses of a few Daltons can be incorporated (Prausnitz, 2008). Other disadvantages also include the possibility of irritation occurring at the site of application which is caused by the drug (Keleb et al, 2010). The greatest disadvantage however is the issue of administering the drug through the skin due to its low permeability. The skin is a protective layer preventing external substances from entering; it allows lipophillic drugs to pass however hydrophilic drugs pass at a much slower rate.
4. Skin Layout, Barriers to Absorption and Routes of Penetration
The human skin (fig 2) is 2-3mm thick and has various layers, each of which contributes towards the skins protective properties, which are further discussed by Ghosh (1997).
As mentioned earlier the major blockade to drug delivery via the skin is the skin itself due to its highly protective function. The major barrier to TDD is the stratum Corneum. This is a layer which is 15-20Âµm thick containing flattened cells and contains keratin within its extracellular lipid. These cells are arranged in a â€œbrick and mortarâ€Â configuration which provides strength and becomes highly impermeable (Keleb et al, 2010).
Fig 2: Routes of Drug Penetration through the skin: 1) through sweat ducts; 2) directly across the stratum corneum; 3) through the hair follicles (Benson, 2005)
There are three main routes by which the skin can be penetrated to allow delivery of drugs:
Through Sweat Ducts
Through hair follicles
Directly through the stratum corneum.
The hair follicles and sweat ducts penetrate through the stratum corneum and therefore allows drugs to pass through, however these only cover approximately 1/1,000 of the skins surface area therefore the amount of drug that can be delivered through this drug is very low (Keleb et al, 2010).
Delivering the drug through the stratum corneum is called the transcellular pathway which involves drug passage through the phospholipid bilayers and the keratin contained within cells, even through this route allows a short distance a greater surface area, penetration is difficult and therefore only a few number of drugs are successful in doing so (Keleb et al, 2010 and Ghosh, 1997).
5.Transdermal Dosage Forms
The advances in TDDs can be categorised in three groups
First Generation Patches:
Second Generation Patches:
Conventional Chemical Enhancers
Non Cavitational Ultrasound
Third Generation Patches:
- Combinations of chemical Enhancers
- Biochemical Enhancers
- Cavitational Ultrasound
- Thermal Ablation
5.1First Generation Patches
The first generation patches are the basic transdermal patches which were initially developed and have been used till date. They are patches which contain a little or no enhancement in their design. They incorporate low molecular drugs which are effective at low doses and are lipophillic in nature.
There are two main systems by which a patch can be designed. The reservoir system or the matrix system.
5.1.1 The Reservoir System
Figure 3: Layout of a reservoir system Transdermal patch (Keleb, 2010)The reservoir system is a system that contains a liquid reservoir in which a drug is dissolved to form a solution or a suspension. It also contains a layer of adhesive and a layer to control the rate of release of the drug (fig 3). The drug then travels through the patch towards the skin by diffusion through these membranes. The rate at which this diffusion of the drug occurs is the rate at which the drug is released and enters the skin.
An example of a reservoir system patch is the testosterone patch (Ghosh, 1997).
5.1.2 The Matrix System
Figure 4: Layout of a matrix system Transdermal patch (Keleb, 2010)The reservoir system consists of drugs which have been mixed with an inert polymer and hence allows controlled release of the drug through the skin. This system is similar to the reservoir system however the two major differences are that the matrix system contains drug reservoir as a semisolid formulation and that it contains no membrane layer (fig 4). The drug, on the other hand similar to the reservoir system will be present in solution form. As there is no membrane layer the drug is in direct contact with the surface of the skin and therefore the rate of drug delivery is controlled by the drugs permeability through the stratum corneum (Ghosh, 1997 and Keleb, 2010).
An example of a patch designed using the matrix system is the ProStep nicotine patch which was brought into the pharmaceutical market in 1991 (table 1).
Other first generation Transdermal formulation which are not in patch form include sprays and gels which are lipophillic in nature and are absorbed upon application for example testosterone gels (Prausnitz, 2008).
5.2 Second Generation Patches
The second generation patches are patches which have a little enhancement in order to facilitate better skin permeability. This can be done by adding an enhancer which reversibly damages the stratum corneum to allow drug passage, provides the formulation with force to allow transport through the skin and ensures no deeper injury is caused (Prausnitz, 2008). However it is not always possible to ensure no damage is caused to deeper tissues therefore second generation patches concentrate on delivery of drug therefore these enhancement techniques are usually used for small drugs for local action, nonetheless there are some advantages in the systemic delivery of macromolecules.
5.2.1 Conventional chemical enhancers
Conventional chemical enhancers, which are added to the formulation in low quantities work by disrupting the layout of the stratum corneum reversibly thereby allowing passage of drug molecules through the skin (Prausnitz, 2008). The layout of the keratin containing cells within the stratum corneum is disrupted by incorporating amphiphillic molecules within the chemical enhancers (Devraj et al 2010), by fluidizing the lipids contained within the stratum corneum, altering cellular proteins or by extracting intracellular lipids (Cui et al, 2008).
The chemical enhancer utilised in the formulation must be non toxic and irritant, ensure its effect on the stratum corneum is rapidly reversible hence hence will allow the API to enter the body however prevent anything from exiting, be compatible with other excipeints and inexpensive (Jampilek et al, 2010).
A the first used enhancer is Azone, which is still utilised till date. It allows incorporation of both hydrophilic and lipophillic drugs (Jampilek et al, 2010 and Ghosh, 1997).
Recent studies have shown that liposome, dendrimers and microemulsions ave also been utilised as chemical enhancers (Devraj et al, 2010). These are advantageous as chemical enhancers as they have a highly complex structure. Currently research is also being carried out in the use of liposomes of delivering insulin via TDD (Prausnitz, 2008).
Iontophoresis involves application of low voltage to the skin through an electrode which contains the API. The oppositely charged electrode will be placed on another location on the body to allow completion of the electrical circuit (Devraj et al, 2010). This increases skin permeability to the drug and also provides an electrical transport mechanism for the drug to cross the statum corneum. This is because charged drugs will be moved due to the electrophoresis whereas weakly charged or uncharged drugs will move indirectly due to the flow of water within the stratum corneum, which is affected by the electrical current (Prausnitz, 2008).
Currently iontophoresis is used to administer patients with local anaesthetics containing lidocaine, pilocarpine and tap water (Devraj et al, 2010). An advantage of this technology is that the electrical currently can be controlled by the patient therefore if they feel uncomfortable or skin irritation occurs they can change the voltage (Prausnitz, 2008).
5.2.3 Non Cavitational Ultrasound
This uses ultrasound to facilitate movement of drugs from the patch through the skin. The ultrasound distrupts the stratum corneum however does not affect any deeper tissue regions. However this is limited to lipophillic, small molecular weight drugs (Prausnitz, 2008).
5.3 Third Generation Patches
The third generation patches include novel techniques which have been developed to enhance drug delivery through the stratum corneum. They have also been developed to enable administration of large molecular weight drug products, proteins and vaccines which is currently in clinical trials (Prausnitz, 2008).
5.3.1 Combinations of Chemical Enhancers
These are chemical enhancers, however they are used in formulation of a TDDs in combinations, which allows the permeability of a specific drug to be enhanced however the damage and irritation to be reduced. For example a combination of Sodium laureth sulphate and phynylpiperazine (Devraj et al, 2010).
5.3.2 Biochemical Enhancers
These are chemical enhancers however they are biological molecules such as proteins or peptides for example magainin. As chemical enhancers they disrupt the stratum corneum and increase the permeability to a drug (Devraj et al, 2010).
This uses high voltage pulses for no longer than a millisecond to disrupt the lipid bilayers in the skin as opposed to inotophoresis which applies a continuous low voltage. This allows the generation of an electron driving force like seen with inotophoresis however it facilitates the transport of macromolecules and protein. This method is not popular for use in humans as over time the resistance presented by the stratum corneum begins to drop and the pulses ultimately begin to affect deeper tissues resulting in pain (Devraj et al, 2010 and Prausnitz, 2008).
5.3.4 Cavitational Ultrasound
Cavitation is the process of forming vapour bubbles and sudden collapse. These cavitaitons can be formed under certain conditions with the aid of ultrasound. The basic principle behind cavitation is that these generated bubbles will collapse upon reaching the surface of the skin, causing vibrations and hence allowing the drug to pass through the stratum corneum. These vibrations increase the permeability of the skin for many hours without causing any damage to tissues within deeper regions (Prausnitz, 2008).
Cavitational ultrasound is used for the delivery of lidocaine and is researched for the administration of insulin through TDDs.
One of the major issues presented by transdermal patches was the inability to allow passage of large molecular weighted drugs. The alternative to create larger pores to facilitate transport of larger molecules was by using microscopic needles to administer drug through the skin. The technology utilises small hyperdermic needles on the patch which pierce the skin painlessly (figure 5) (prausnitz, 2004).
The general mode of action of microneedles is to increase the permeability of the skin with the aid of the microneedles, transport drug into the skin via the pores created by the needles and to ultimately target the stratum corneum (Prausnitz 2008).
Figure 5: Microneedles on a Transdermal patch (Prausnitz, 2008)There are three methods by which a drug can be administered to a patient via a patch containing microneedles:
Poke with Patch
Coat and poke
Dip and scrape
The poke and patch method is using microneedles on a patch made out of silicon or metal to pierce holes on the skin and then applying a patch of drug on the skin to allow drug to diffuse through the stratum corneum. An example of the poke and patch method is in clinical trials for the delivery of insulin (Prausnitz, 2008 and Prausnitz 2004).
Figure 6: Blunt microneedles on a Transdermal patch (Prausnitz, 2008)The coat and poke method consists of coating the microneedles on the patch with the drug required to be administered and then applying the patch to the skin, unlike the first generation patches developed these patches contain no reservoir system, all drug that is required to be administered to the patient will be coated on to the microneedles themselves (Prausnitz 2004). Research was carried out for the administration of protein ovalbumin by Matriano et al (2002), to produce a vaccine using the TDDs technology (Prausnitz 2004).
The dip and scrape method is similar to the coat and poke method whereby the needles are dipped into the drug and then instead of applying the patch on to the skin it is scrapped and the drug is left behind for absorption (Prausnitz 2004). This method can be used to create DNA vaccines which was studies by mikszta et al (2002) which utilised blunt tipped microneedles (figure 6) to scrape the skin and administer the DNA vaccine (Mikszta et al, 2002).
Hollow microneedles (figure 7) are also being studied to allow administration of liquid drugs through holes in the needles. These can be made out of glass which was studied by McAllister et al on diabetic rats. (Prausnitz 2004).
Prausnitz (2008) also comments on the recent studies carried out which involved applying a microneedle patch containing naltrexone and commented on the well received feedback of volunteers. The method of microneedle patches was painless and drug plasma concentration of naltrexone reached its therapeutic index.
Figure 7: Hollow microneedles on a Transdermal patch (Prausnitz, 2008)
5.3.6 Thermal Ablation
This method unlike any method developed uses heal to enhance the permeability of the skin. It heats the skin to over a hundred degree for microseconds, the heat results in water evaporation from the stratum corneum resulting in expansion between the cells and facilitating drug transfer. Studies on animals have shown that drugs such as human growth hormones and insulin can be administered in such a way (Prausnitz (2008).
6. Excipients Incorporated during Formulation
An ideal TDDs is required to have a shelf life of up to 2 years, a size of less than 40cm2, a low dosage interval (once daily to once a week), not an obvious colour (clear, tan or white), easily removed from packaging and easily applied to skin, non irritating to patient and its drug release properties should be constant (Keleb et al 2010).
As shown by figure 1 a transdermal patch is composed of a backing, reservoir, adhesive and the API.
6.1 Backing films
The films used are usually synthetic polymers such as polyester or polyethylene or natural polymers such as cotton or wool, depending on the API to be incorporated in to the formulation. The main objective of the backing film is to prevent the API from leaking out of the formulation and contamination from entering the formulation. They also facilitate printing and therefore allow unique identification of the patch applied (Ghosh 1997).
A polymer is incorporated into the formulation to control the rate of release of the drug. These can be natural polymers such as gelatine and starch or can be synthetic polymers such as polyvinyl alcohol and polyvinyl chloride. The polymers utilised are lipophillic or hydrophilic depending on the drug incorporated (Ghosh 1997).
An adhesive needs to be able to adhere to the skin with enough force but still remain easily peel able, should leave little or washable residue on the skin, should not irritate the patient, must be compatible with other excipients incorporated into the formulation and should not affect the drugs properties (Ghosh 1997).
It can be seen that all first generation Transdermal patches are designed to deliver drugs which are lipophillic in nature and are small in size compared to the second and third generation drugs which not only allow easier transport of small drug molecules through the skin by the use of enhansers but also facilitate the administration of larger molecular weighted drugs.
The administration of a drug via Transdermal route needs to be safe and effective therefore there needs to be a well established balance on how enhanced a second or third generation Transdermal patch can be otherwise there would be higher amounts of side effects associated with application of the patch.
In the future Transdermal drug delivery will develop to provide more drugs via this route in a more safe and effective manner