More than 35 TDD products have now been approved for sale in the US, and approximately 16 active ingredients are approved for use in TDD products globally. TDD product sales in the US have increased by 23% from 2000 to 2001 and by 9% over the same time period in Europe

Fig 1: Global sales among TDD Product

MYTH 2:

Transdermal drug delivery is an old technology.

Interest exists in expanding the function and capabilities of Transdermal drug delivery, with many significant innovations in TDD technologies occurring only over the past decade. Where are the innovations in Transdermal drug delivery occurring Most can be divided into two categories: system innovations and formulation innovations. Most system innovations involve technologies that use various energy sources to increase drug flux across the skin.

MYTH 3:

All drugs that can be delivered transversally are already on the market.

In the first section, it was discussed that the Transdermal drug delivery market is growing and that there is a prospect for higher growth in this market over the next several years based on the strong pipeline of Transdermal products in clinical development in the US. Clearly, the opportunities for Transdermal drug delivery have been greatly expanded through the application of new formulation technologies and active delivery systems.

MYTH 4:

Transdermal drug delivery systems are not suitable for delivery of biotechnology drugs, such as protein/peptide pharmaceuticals.

New Transdermal technologies are being developed that greatly expand the range of molecules that can be delivered transversally. While it is true that the molecular size and solubility characteristics of biopharmaceuticals, such as proteins, peptides, and carbohydrates, prevent their passage through the skin, which is a quite efficient membrane for preventing transport of macromolecules, and preclude their use within typical passive Transdermal systems, newer Transdermal technologies are making progress in overcoming this barrier. Several new Transdermal technologies incorporate mechanisms to transiently circumvent the normal barrier function of the skin and to allow two of the better-known technologies are iontophoresis and sonophoresis. Both of these the passage of macromolecules.

COMPONENTS OF TRANSDERMAL PATCH:

· Liner - Protects the patch during storage. The liner is removed prior to use.

· Drug - Drug solution in direct contact with release liner.

· Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin.

· Membrane - Controls the release of the drug from the reservoir and multi- Layer patches.

· Backing - Protects the patch from the outer environment.

COMPONENTS OF TDDS

Polymer matrix / Drug reservoir

· Drug

· Permeation enhancers

· Pressure sensitive adhesive (PSA)

· Backing laminates

· Release liner

· Other recipients like plasticizers and solvents

Polymer matrix / Drug reservoir:

Polymers are the backbone of TDDS, which control the release of the drug from the device. Polymer matrix can be prepared by dispersion of drug in liquid or solid state synthetic polymer base. Polymers used in TDDS should have biocompatibility and chemical compatibility with the drug and other components of the system such as penetration enhancers and PSAs.

Drug: The Transdermal route is an extremely attractive option for the drugs with appropriate pharmacology and physical chemistry. Transdermal patches offer much to drugs which undergo extensive first pass metabolism, drugs with narrow therapeutic window, or drugs with short half life which causes non- compliance due to frequent dosing. the drugs for Transdermal delivery. In addition drugs like rivastigmine for Alzheimer’s and Parkinson dementia, retightened for Parkinson, methylphenidate for attention deficit hyperactive disorder and elegizing for depression are recently approved as TDDS.

Permeation Enhancers:

These are the chemical compounds that increase permeability of stratum corneas so as to attain higher therapeutic levels of the drug candidate³². Penetration enhancers interact with structural components of stratum conium i.e., proteins or lipids. They alter the protein and lipid packaging of stratum conium, thus chemically modifying the barrier functions leading to increased permeability

Pressure sensitive adhesives:

A PSA is a material that helps in maintaining an intimate contact between Transdermal system and the skin surface. It should adhere with not more than applied finger pressure, be aggressively and permanently tacky, exert a strong holding force. Additionally, it should be removable from the smooth surface without leaving a residue. Polyacrylates, polyisobutylene and silicon based adhesives are widely used in Todd’s.

Release Liner:

During storage the patch is covered by a protective liner that is removed and discharged immediately before the application of the patch to skin. It is therefore regarded as a part of the primary packaging material rather than a part of dosage form for delivering the drug.

Other excipients:

Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir.In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch

TYPES OF TRANSDERMAL PATCHES:

a) Single layer drug in adhesive: In this type the adhesive layer contains the drug. The adhesive layer not only serves to adhere the various layers together and also responsible for the releasing the drug to the skin. The adhesive layer is surrounded by a temporary liner and a backing.

b) Multi -layer drug in adhesive: This type is also similar to the single layer but it contains an immediate drug release layer and other layer will be a controlled release along with the adhesive layer. The adhesive layer is responsible for the releasing of the drug. This patch also has a temporary liner-layer and a permanent backing

c) Vapour patch: In this type of patch the role of adhesive layer not only serves to adhere the various layers together but also serves as release vapor. The vapor patches are new to the market,.

d) Reservoir system: In this system the drug reservoir is embedded between an impervious backing layer and a rate controlling membrane. The drug releases only through the rate controlling membrane, which can be micro porous or non porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed in a solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is compatible with drug.

e) Microreservoir system: In this type the drug delivery system is a combination of reservoir and matrix-dispersion system. The drug reservoir is formed by first suspending the drug in an aqueous solution of water soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unreachable, microscopic spheres of drug reservoirs. This thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ by using cross linking agents.

VARIOUS METHODS FOR PREPARATION TDDS:

· Asymmetric TPX membrane method:

A prototype patch can be fabricated for this a heat sealable polyester film (type 1009, 3m) with a concave of 1cm diameter will be used as the backing membrane. Drug sample is dispensed into the concave membrane, covered by a TPX {poly(4-methyl-1-pentene)}asymmetric membrane, and sealed by an adhesive. [(Asymmetric TPX membrane preparation): These are fabricated by using the dry/wet inversion process. TPX is dissolved in a mixture of solvent (cyclohexane) and nonsolvent additives at 60°c to form a polymer solution.

· Circular teflon mould method:

Solutions containing polymers in various ratios are used in an organic solvent. Calculated amount of drug is dissolved in half the quantity of same organic solvent. Enhancers in different concentrations are dissolved in the other half of the organic solvent and then added. Di-N-butylphthalate is added as a plasticizer into drug polymer solution. The total contents are to be stirred for 12 hrs and then poured into a circular Teflon mould. The moulds are to be placed on a leveled surface and covered with inverted funnel to control solvent vaporization in a laminar flow hood model with an air speed of 0.5 m/s. The solvent is allowed to evaporate for 24 hrs.

· Mercury substrate method:

In this method drug is dissolved in polymer solution along with plasticizer. The above solution is to be stirred for 10- 15 minutes to produce a homogenous dispersion and poured in to a leveled mercury surface, covered with inverted funnel to control solvent evaporation.

EVALUATION OF TRANSDERMAL PATCHES:

Development of controlled release transdermal dosage form is a complex process involving extensive research. Transdermal patches have been developed to improve clinical efficacy of the drug and to enhance patient compliance by delivering smaller amount of drug at a predetermined rate. This makes evaluation studies even more important in order to ensure their desired performance and reproducibility under the specified environmental conditions. These studies are predictive of transdermal dosage forms and can be classified into following types:

· Physicochemical evaluation

· In vitro evaluation

· In vivo evaluation

Upon the success of physicochemical and in vitro studies, in vivo evaluations may be conducted.

PHYSICOCHEMICAL EVALUATION:

Thickness: The thickness of transdermal film is determined by traveling microscope, dial gauge, screw gauge or micrometer at different points of the film.

Uniformity of weight: Weight variation is studied by individually weighing 10 randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight

Drug content determination: An accurately weighed portion of film (about 100 mg) is dissolved in 100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker incubator. Then the whole solution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically by appropriate dilution.

Moisture content: The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 h. The films are weighed again after a specified interval until they show a constant weight

IN VITRO RELEASE STUDIES:

Drug release mechanisms and kinetics are two characteristics of the dosage forms which play an important role in describing the drug dissolution profile from a controlled release dosage forms and hence their in vivo performance. A number of mathematical model have been developed to describe the drug dissolution kinetics from controlled release drug delivery system

There are various methods available for determination of drug release rate of TDDS.

· The Paddle over Disc: (USP apparatus 5/ PhEur 2.9.4.1) This method is identical to the USP paddle dissolution apparatus, except that the transdermal system is attached to a disc or cell resting at the bottom of the vessel which contains medium at 32 ±5°C

· The Cylinder modified USP Basket: (USP apparatus 6 / PhEur 2.9.4.3) this method is similar to the USP basket type dissolution apparatus, except that the system is attached to the surface of a hollow cylinder immersed in medium at 32 ±5°C

The amount of drug available for absorption to the systemic pool is greatly dependent on drug released from the polymeric transdermal films. The drug reached at skin surface is then passed to the dermal microcirculation by penetration through cells of epidermis, between the cells of epidermis through skin appendages.

Preparation of skin for permeation studies: Hairless animal skin and human cadaver skin are used for permeation studies. Human cadaver skin may be a logical choice as the skin model because the final product will be used in humans. But it is not easily available. So, hairless animal skin is generally favored as it is easily obtained from animals of specific age group or sex.

IN VIVO STUDIES:

In vivo evaluations are the true depiction of the drug performance. The variables which cannot be taken into account during in vitro studies can be fully explored during in vivo studies. In vivo evaluation of TDDS can be carried out using:

ANIMAL MODELS:

Human volunteers:

Animal models Considerable time and resources are required to carry out human studies, so animal studies are preferred at small scale. The most common animal species used for evaluating transdermal drug delivery system are mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig etc. Various experiments conducted lead us to a conclusion that hairless animals are preferred over hairy animals in both in vitro and in vivo experiments. Rhesus monkey is one of the most reliable models for in vivo evaluation of transdermal drug delivery in man.

Human models The final stage of the development of a transdermal device involves collection of pharmacokinetic and pharmacodynamic data following application of the patch to human volunteers. Clinical trials have been conducted to assess the efficacy, risk involved, side effects, patient compliance etc. Phase I clinical trials are conducted to determine mainly safety in volunteers and phase II clinical trials determine short term safety and mainly effectiveness in patients. Phase III trials indicate the safety and effectiveness in large number of patient population and phase IV trials at post marketing surveillance are done for marketed patches to detect adverse drug reactions.

Stability studies: The stability studies are conducted to investigate the influence of temperature and relative humidity on the drug content in different formulations. The transdermal formulations are subjected to stability studies as per ICH guidelines.

CONCLUSION:

Since 1981, transdermal drug delivery systems have been used as safe and effective drug delivery devices. Their potential role in controlled release is being globally exploited by the scientists with high rate of attainment. If a drug has right mix of physical chemistry and pharmacology, transdermal delivery is a remarkable effective route of administration. Due to large advantages of the TDDS, many new researches are going on in the present day to incorporate newer drugs via the system. A transdermal patch has several basic components like drug reservoirs, liners, adherents, permeation enhancers, backing laminates, plasticizers and solvents, which play a vital role in the release of drug via skin. Transdermal patches can be divided into various types like matrix, reservoir, membrane matrix hybrid, micro reservoir type and drug in adhesive type transdermal patches and different methods are used to prepare these patches by using basic components of TDDS. After preparation of transdermal patches, they are evaluated for physicochemical studies, in vitro permeation studies, skin irritation studies, animal studies, human studies and stability studies. But all prepared and evaluated transdermal patches must receive approval from FDA before sale. Future developments of TDDSs will likely focus on the increased control of therapeutic regimens and the continuing expansion of drugs available for use. Transdermal dosage forms may provide clinicians an opportunity to offer more therapeutic options to their patients to optimize their care.

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Received on 21.07.2011

Modified on 20.08.2011

Accepted on 10.10.2011

Research J. Science and Tech. 3(6): Sept.-Oct. 2011: 227-231