Pressure Wave : For Enhancement of Transdermal Permeation

Anupam Nayak

Pressure wave are generated by the intense laser radiation and can permeabilize the stratum corneum and cell membrane, it allow macromolecules to diffuse stratum corneum and facilitate the transdermal drug transport through the skin.

The ultimate aim of every therapy is to restore the normalcy of life, but ironically sometimes, the requirements of treatment are such that the normal rhythm of life is disturbed. Skin represents a very important route of drug delivery. When the first patch of scopolamine approved in 1979 the transdermal delivery had been become an interest of researcher. Today there exists a number of patches for drugs such as scopolamine, nitroglycerin, nicotine, clonidine, fentanyl, estradiol, testosterone, lidocaine, and oxybutinin. As the medication becomes the integral part of life, the success of the therapy depends on patient compliance too. Since Transdermal dosage forms can minimize the fluctuations of plasma level and increase patient compliance, the development of the transdermal dosage form of for this has become research interest.

For several decades, there has been interest in using the skin as a port of entry into the body for the systemic delivery of therapeutic agents. As both the largest and most visible organ of the body, the skin is of unequalled importance in portraying an individual’s state of being. Human skin consists of three main layers—the epidermis, dermis and hypodermis. The dermis is vascularised and the thickest of all the layers (3–5 mm thick). It possesses sweat glands, hair follicles, nerve endings and lymph vessels and acts as the systemic absorption site for drugs. The epidermis, however, constitutes the rate-limiting layer for transdermal absorption of drugs (thickness varies from 0.06 mm on eyelids to 0.8 mm on soles of palms/feet). The major barrier to permeation resides in the uppermost of the five layers of the epidermis, the stratum corneum. It is approximately 10–20 μm thick (depending on hydration level) and acts as a protective membrane preventing water loss from the skin and limiting the ingress of chemicals from the environment.

Problem associated with the barrier properties of the skin transdermal delivery is limited to number of drug molecule only. To overcoming these problems a number of approaches has been made such as chemical enhancers, ultrasound, electricity, ultrasound, microneedle, and pressure wave for enhancing the transdermal drug delivery. This review is concern with pressure wave assisted transdermal drug delivery.

Pressure wave are generated by the intense laser radiation and can permeabilize the stratum corneum and cell membrane, it allow macromolecules to diffuse stratum corneum and facilitate the transdermal drug transport through the skin. Pressure wave can be generated by optical breakdown, ablation, or rapid heating of an absorbing medium (thermo elastic generation). Among these ablation is the reliable method for generating pressure waves. In ablation the laser radiation causes decomposition of the target material into small fragments, which move away from the surface of the target at supersonic speed.

Experiment arrangement: Doukas et al ( 2003) performed an experiment arrangement was made as following:

-A rubber washer was attached to the skin with grease, was used as a reservoir for the solution to be delivering through the stratum corneum.

-The target material (black polystyrene) was placed on top of the washer in contact with the solution to generate the pressure waveby ablation.

-The articulating arm of the laser was positioned over the target and laser fired once to generate pressure wave.

-The pressure wavepropagated through the drug solution which also act as acoustic coupling medium, impinged on the skin and permeablized the stratum corneum.

-The molecule diffused into the viable epidermis under the concentration gradients through the channel produced by pressure wave. The barrier function of the skin always recovered.

-In the last the target and the washer were removed and the skin was wiped clean.

Figure: Enhancement of transdermal permeation by pressure wave

-The permeabilization of the stratum corneum depended on the peak pressure. The onset of the permeabilization of the stratum corneum was observed at about 350 bar and increased with increasing pressure.

-The mechanism of the permeabilization is probably caused by the disruption of the hydrophilic domains of the stratum corneum.

Characterization of Pressure Wave:

The characteristics of the pressure wave (peak pressure, rise time and duration) depend on the laser parameters (wavelength, pulse duration and fluence) and the optical and mechanical properties of the target material. The efficiency of the pressure wave generation, conversion of light energy to the mechanical energy of the pressure wave, is given by the coupling coefficient. The coupling coefficient is defined as the total momentum transfer to the target during ablation divided by the laser pulse energy. From the coupling coefficient the peak pressure can be calculated. The equation given below gives the peak pressure generated during ablation of polymers and metals as a function of irradiance, wavelength and pulse duration.

P₀ = b {I ^0.7/ (λ√ t)^0.3}

where P is the peak pressure of the wave, b the proportionality constant which depends on the material properties, I the laser irradiance, λ the laser wavelength and t the laser pulse duration.

Advantages: Various advantages suggested for pressure wave mediated transdermal drug delivery as following:

- The pressure wave is applied for a very short time (100 ns-1µs). the pressure wavedose note transport the drug through stratum corneum. It only transiently permeabilized the stratum corneum. The delivery of the drug takes place by diffusion under the concentration gradients. (Doukas et al, 2003)

- The application of pressure wavedid not cause any pain or discomfort. ( lee et al, 1999)

-The permeability of the stratum corneum is depending on the duration of pressure wave. (Lee et al, 2001)

-The recovery of the barrier function can be easily modulated by changing the characteristics of the pressure wave.

-Controlled drug delivery possible.

-Pressure wave can be thought of as a generic technology platform for the drug delivery into many different biological systems (skin, cell, microbial biofilm)

Research in pressure wave mediated transdermal drug delivery:

Lee et al (1996) worked on “Alteration of cell membrane permeability by laser-induced stress waves in vitro” and shown that pressure wave permeabilzed the cell plasma membrane and allow the macromolecules to diffused through it into the cytoplasm.

Further lee et al (1998) worked on “Photomechanical transcutaneous delivery of macromolecules’ and suggest pressure wave permeablized the stratum corneum and facilitate the transport of macromolecules into the viable skin.

Soukos et al (2000) have been shown ‘Photomechanical drug delivery into microbial biofilms”

Lin et al (2003) have been worked on “Nuclear transport by laser-induced pressure transients” and suggest pressure wave can permeabilized the nuclear envelop and facilitate the delivery of macromolecules into the cell nucleus.

Doukas et al (1993) worked under the title “Biological effects of laser-induced shock waves: structural and functional cell damage in vitro” further same group (1995) have seen , Physical factors involved in stress-wave-induced cell injury: the effect of stress gradient.

Lee et al (1999) have studied on “Laser-generated stress waves and their effects on the cell membrane”

Gonza´lez (2001) have been shown “Rapid antigen delivery with photomechanical waves for inducing allergic skin reaction in the DNCB-sensitized hairless guinea pig animal model.” Results shown that there was an allergic reaction for the 24 hours occlusion or photomechanical delivery of the antigen. In contrast no response was observed for the 5 minute occlusion with the antigen.

Soukos et al ( 2000) Photomechanical Drug Delivery into Bacterial Biofilms Results suggest that a single photomechanical wave was sufficient to induce a 75% increase in the penetration depth of methylene blue into the biofilm. This significantly increased the concentration of methylene blue in the biofilm enablingits photodestruction.

Lee et el ( 1999) asses the feasibility of in vivo topical drug delivery in humans with a single photomechanical wave. And suggest that the dose delivered across the stratum corneum depends on the peak pressure and has a threshold at around 350 bar. A 30% increase in peak pressure, produced a 680% in the amount delivered.

Recently Ogura et al (2007) worked on “photomechanical wave assisted molecular delivery in oral biofilm’ results suggest that the pressure wave enhanced the penetration depth of methylene blue in biofilm.

Conclusion:

Photomechanical waves provide a potentially powerful tool for enhancement of permeation in transdermal drug delivery.

References:

[1] Makoto Ogura, Abraham D. Abernethy Ryan D., Blissett , Karriann Ruggiero, Sovanda SomJ. Max Goodson, Ralph Kent, Apostolos G. DoukasNikolaos S. Soukos. Photomechanical wave-assisted molecular delivery in oral biofilms. World J Microbiol Biotechnol (2007) 23:1637–1646.

[2] Nikolaos S. Soukos, Sigmund S. Socransky, Stephen E. Mulholland, Shun Lee, and Apostolos G. Doukas. Photomechanical Drug Delivery into Bacterial Biofilms. Pharmaceutical Research, Vol. 17, No. 4, 2000

[3] S. Gonza´lez, S. Lee, E. Gonza´lez, A.G. Doukas, Rapid antigen delivery with photomechanical waves for inducing allergic skin reaction in the DNCB-sensitized hairless guinea pig animal model, Am. J. Contact Dermatol. 12 (2001) 162–165.

[4] T.-Y.D. Lin, D.J. McAuliffe, N. Michaud , H. Zhang, S. Lee, A.G. Doukas, T.J. Flotte, Nuclear transport by laser-induced pressure transients. Pharm. Res. 20 (2003) 879– 883.

[5] Apostolos G. Doukasa, Nikiforos Kolliasb. Transdermal drug delivery with a pressure wave Advanced Drug Delivery Reviews 56 (2004) 559 – 579

[6] A.G. Doukas, D.J. McAuliffe, T.J. Flotte, Biological effects of laser-induced shock waves: structural and functional cell damage in vitro, Ultrasound Med. Biol. 19 (1993) 137– 146.

[7] A.G. Doukas, D.J. McAuliffe, S. Lee, V. Venugopalan, T.J. Flotte, Physical factors involved in stress-wave-induced cell injury: the effect of stress gradient, Ultrasound Med. Biol. 21 (1995) 961–967.

[8] S. Lee, A.G. Doukas, Laser-generated stress waves and their effects on the cell membrane, IEEE J. Select. Topics Quant. Electr. 5(1999) 997– 1003.

[9] N.S. Soukos, S.S. Socransky, S.E. Mulholland, S. Lee, A.G. Doukas,Photomechanical drug delivery into microbial biofilms, Pharm. Res. 17 (2000) 405– 409

[10] S. Lee, D.J. McAuliffe, T.J. Flotte, N. Kollias, A.G. Doukas, A.G. Doukas, N. Kollias / Advanced Drug Delivery Reviews 56 (2004) 559–579 577 Photomechanical transcutaneous delivery of macromolecules, J. Invest. Dermatol. 111 (1998) 925–929

[11] S. Lee, T. Anderson, H. Zhang, T.J. Flotte, A.G. Doukas, Alteration of cell membrane permeability by laser-induced stress waves in vitro, Ultrasound Med. Biol. 22 (1996) 1285– 1293

[12] S. Lee, N. Kollias, D.J. McAuliffe, T.J. Flotte, A.G. Doukas Topical drug delivery in humans with a single photomechan Topical drug delivery in humans with a single photomechan ical wave, Pharm. Res. 16 (1999) 1717 – 1721

[13] S. Lee, D.J. McAuliffe, T.J. Flotte, N. Kollias, A.G. Doukas Photomechanical transdermal delivery: the effect of laser con- finement, Lasers Surg. Med. 28 (2001) 344 – 347

[14] C.R. Phipps Jr., T.P. Turner, R.F. Harrison, G.W. York, W.Z. Osborne, G.K. Anderson, X.F. Corlis, L.C. Haynes, H.S.Steele, K.C. Spicochi, T.R. King, Impulse coupling targets in vacuum by KrF, HF, and CO2 single pulse laser, J. Appl. Phys. 64 (1988) 1083– 1096

About Authors:

Mr. Anupam Nayak is a final year B.Pharma student of Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India.
Corresponding Author E-mail: annunayak01@yahoo.co.in
Contact no.: +919755920721

Mr Ashish Jain (M.Pharm, Pursuing PhD), Department of Pharmaceutics and Pharmaceutical Technology, Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India.
E-mail: aashish.pharmatech@gmail.com
Mob. No. +919981574693

Mr Piyush tiwari (M.Pharm), Department of Pharmaceutics and Pharmaceutical Technology, Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India. Email: piyush.tiwarig@gmail.com

Dr. Satish Nayak (M.Pharma, PhD), Principal, Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India. He earned his Ph.D in pharmacogonosy. Dr. Satish Nayak has 18 years of academic and research experience. He has more than 30 national and international research papers to his credit.