b.)PHYSICAL MEANS:

1.         PHONOSORESIS(SONOPHORESIS):
 It is defined as the movement of drugs through intact skin & underlying soft tissues under the influence of an ultrasonic perturbation. It is safe technique for enhancing drug administration & is effective in clinical applications when with a proper frequency, power level, and duration. It increases drug permeation through the skin by disordering the structured lipids in the stratum corneum. Applications of low-frequency (20 KHz) ultrasound enhances transdermal transport of high-molecular weight proteins. Ultrasound based on hypothesis that if cavitation plays an important role in ultrasound-facilitated skin permeation, & since the cavitation threshold (i.e., the minimal ultrasound intensity required to cause cavitation) increases rapidly with an increase of ultrasound frequency’ lower frequency would cause more cavitation and hence, higher skin Permeation of a drug.  Many conventional sonophoresis devices have been developed and they are categorized into basic types, namely the disk-type and the horn-type.Ultrasonic energy delivered from devices is being used to enhance therapeutic efficacy in the treatment of local conditions by a process of phonosoresis and sonosoresis. Current research is applied on synergistic or additive effect. In addition, a sample of interstitial fluid or its components may be extracted through permeabilized skin for diagnostic applications.

2. IONTOPHORESIS
There has been a growing awareness in recent years of potential therapeutic importance of achieving true controlled drug delivery where the rate of drug output may be modulated in a precisely controlled manner. Transdermal drug delivery has usefulness in achieving the controlled delivery of pharmaceuticals, which are relatively small in molecular size and rather lipophilic in nature, however, these systems are rather limited in their capability of achieving the transdermal systemic delivery of peptides, proteins and drugs which is often charged and highly hydrophilic in nature. In order to deliver an ionic drug, peptide/protein molecule through transdermal delivery to attain a systemic effect, and chemical and/or physical methods is required to enhance the rate of penetration of therapeutic agent through the main diffusion barrier. The intophoratic technique is highly desirable to improve the transdermal delivery of peptide and proteins using a lower current intensity with a short time period. The idea of applying electric current to increase the penetration of electrically charged drugs into surface tissues was probably organized by Veratti in 1947. Leduc did the first well-documented experiments at the beginning of the 20th century. Leduc demonstrated the introduction of strychnine and cyanide ions into the rabbits when the correct polarities were applied.  By the process of electromigration and electro-osmosis, iontophoresis increases the permeation of charged and neutral compounds, and offers the option for programmed drug delivery. Interest in this field of research has led to the successful delivery of both low (lidocaine) and high molecular drugs, such as peptides (e.g., luteinising hormone releasing hormone, nafarelin and insulin). Combinations of iontophoresis with chemical enhancers, electroporation and sonophoresis have been tested in order to further increase transdermal drug permeation and decrease possible side effects. In addition, rapid progress in the fields of microelectronics, nanotechnology and miniaturisation of devices is leading the way to more sophisticated iontophoretic devices, allowing improved designs with better control of drug delivery.    

3. ELECTROPORATION
 It is a phenomenon in which the membrane of a cell exposed to high-intensity electric field pulses(up to several hundred volts for micro- or milliseconds) can be temporarily, thus becoming highly permeable to exogenous molecules in the surrounding media. A recent report provide a theoretical analysis according to which ,charged molecules were considered transporting through existing shunt routes of the skin at transdermal voltage <100 v. when transdermal voltage was greater than 100v, the transcorneocyte pathway was also accessible to charged molecules as lipid bilayers were electroporated.Synergistic effect was shown by ultrasound and electric field than positive of electric field only. Research is doing for effective, safe, cost-effective, as well as powerfully versatile (e.g., microchip controlled for complex drug delivery patterns).