MICROCHANNEL BASED TRANSDERMAL DELIVERY USING RADIO FREQUENCY: A NOVEL APPROACH

1. MICROCHANNEL BASED TRANSDERMAL DELIVERY USING RADIO FREQUENCY: A NOVEL APPROACH Author Co-author Name : Parikh AnkitkumarYogeshbhai. College: Institute of pharmacy; Nirma university, Year: 4th year E mail id: ankit_parikh_22889@yahoo.co.in Profile link: http://www.pharmainfo.net/ankit Name: Shah Jigar Nareshkumar - Faculty College: Institute of Pharmacy, Nirma University, Ahmedabad. Email id: jigs_12@rediffmail.com, jigar.shah@nirmauni.ac.in Profile link: http://www.pharmainfo.net/jigsh12

2. Drug Particles Introduction DEFINATION: Transdermal permeation (percutaneous absorption): • The passage of substance from the outside of the skin through its various layers into the bloodstream. • Transdermal permeation • Transdermal permeation

3. Basic Advantages of transdermal delivery system • Avoids first-pass effect • Allows effective use of drugs with short biological half-life • Allow administration of drugs with narrow therapeutic window • Provides controlled plasma level of very potent drugs • Drug input can be promptly interrupted when toxicity occurs • Increased patient compliance

4. Disadvantages of TDS • Drug that require high blood levels cannot be administered • Adhesive may not adhere well to all types of skin • Drug or drug formulation may cause skin irritation or sensitization • Uncomfortable to wear • May not be economical.

5. Factors Consideration for TDS development • Skin Characteristics • Bioactivity of drug • Formulation • Adhesion • System design

6. The Structure of Human Skin:

7. Factor influence the transdermal route • Time scale of permeation (steady-state vs. transient diffusion) • Physicochemical properties of penetrant (pKa, molecular size, stability, binding affinity, solubility, partition coefficient) • Integrity and thickness of stratum corneum • Density of sweat glands and folicles • Skin hydration • Metabolism • Vehicle effects

8. Process of transdermal permeation

9. Various approaches Various approches Active Passive Suffers from various limitations, primarily due to lack of permeability of many drugs & skin nature. Iontophoresis Electroporation Microchannel based system Micro -needle Rf systems

10. Various Approaches a)Transdermal diffusion, possibly in the presence of a chemical enhancer, takes place by a tortuous route across the stratum corneum, winding around cells and occurring along the interfaces of extracellular lipid bilayers. b) Low-voltage electrical enhancement by iontophoresis can make transport pathways through hair follicles and sweat ducts more accessible. c) High-voltage enhancement by electroporation has been shown to occur via transcellular pathways made accessible by disrupting lipid bilayers. The application of ultrasound seems to make pathways a and c more permeable by disorganizing lipid bilayer structure. d)Microneedles and RF cell ablation create micron-scale holes in skin to provide pathways for drug transport.

11. Limitation of passive & various active drug delivery system • Most of the methods suitable for small molecules • Not practical enough to offer viable solutions for pharmaceutical needs. This is due to various limitations such as an insufficient delivered dose or duration of delivery. • Electric charge required (Iontophoresis) • Required pH environment for effective delivery of drug

12. Micro channel based trans delivery system using RF • A novel system for active transdermal drug delivery, based on creating microchannels in the skin using radio-frequency (RF) electrical current. • This novel and unique approach provides various advantages such as; - A predicted and precisely controlled drug delivery rate, - Efficient delivery of a wide range of molecular sizes including proteins and other macromolecules, - A convenient, pain-free system suitable for self application at home.

13. Micro channel based trans delivery system using RF

14. Principle • It is based on principle of RF ablation, a well-known medical technology to eliminate living cells which used to cut through tissues in minimally invasive operations or to destroy small tumors in the kidney and liver by passing an alternating electrical current at a frequency above 100 KHz (radio frequency) through the area.

15. Method Application of RF device by placing a closely spaced array of tiny electrodes with very precise dimensions against the skin Alternating electrical current is transferred through each of the microelectrodes Cell ablation and form the microscopic passage Application of transdermal patch and microchannels serve as aquatic channels into the inner layers of the skin Formation of RF microchannels with consistent, well-controlled depths

16. electrode Passig current patch Formationofmicrochannel Release of drug

17. Drug delivery device • The system consists of the device, which is used to pretreat the skin and form the RF microchannels in the outer layers of the skin, and a patch containing the drug, which is placed on top of the pretreated skin. (a) THE DEVICE (b) THE MICROELECTRODE ARRAY (c) THE PATCH

18. Stained microchannel

19. Effect of patch technology on pharmacokinetic profiles: • For drug delivery, the microchannels may last up to 24 h. At 36 h, the delivery through treated skin returns to the values of intact skin. • To achieve a sustained drug flux for 24 h, incorporating the active material into a moist matrix such as a hydrogel that serves as an infinite reservoir. • The study was conducted on six healthy adult volunteers in each test group by Galit Levin. The results revealed differences in the plasma-drug levels and profiles between the treatments.

20. Effect of patch technology on pharmacokinetic profiles • The results revealed differences in the plasma-drug levels and profiles between the treatments studied by Galit Levin.

21. Effect of patch technology on pharmacokinetic profiles • The transdermal delivery through microchannels resulted in a concentration increase up to 9h and a constant level up to 24 h. • This finding confirms that RF microchannel formation is uniform and reproducible. • A microelectronic system based on RF cell ablation using printed-protein patches resulted in very high bioavailability of up to 40%.

22. Effect of patch technology on pharmacokinetic profiles Table shows the bioavailability of three drug molecules studied by Galit Levin.

23. Factors influences this system: • Molecular size of the molecule delivered • Water solubility • Concentration • Microchannel density • Duration of delivery • Dosage forms • Drug profile • Type of patches • Drug accumulation.

24. Factors influences this system • Molecular size:In case of small-molecule drugs, size can be increased significantly by pretreatment & for macromolecules, like peptides and proteins, also help in delivering them systemically through the skin by this technology. • Water solubility:Water-soluble molecules, can be easily delivered. Water-insoluble drugs can be delivered by increasing the water solubility through a suitable formulation. • Concentration:In contrast to any passive delivery, It is help in increasing the drug concentration on the skin in the vicinity of the microchannels will result in a higher delivery rate.

25. Factors influences this system • Microchannel density:By increasing the microchannel density (MCs/cm2 ), a higher amount of drug can be delivered in efficient manner. • Duration of delivery:The drug delivery can be enhanced up to 24 h using this technology • Dosage forms:A patch is the most convenient dosage form for drug delivery. Beside this, gels, Creams & the other semisolid dosage forms can be used. • Drug profile: The result of the transdermal delivery using RF cell ablation can be a peak-plasma profile or a constant blood level, depending on the type of patch technology used

26. Factors influences this system • Type of patches: A reservoir patch, usually a water-based hydrogel, can be used to incorporate small or large molecules and apply them on the skin. For proteins, the use of a printed patch is advisable for stability purposes. • Lack of reservoir in the skin:In contrast to passive delivery, the microelectronic system based on RF cell ablation used in this study delivered water-soluble drugs that cannot be accumulated in the lipidic stratum corneum. No issue of reservoir formation exists.

27. Main Application For protein delivery For hydrophilic drug & hydrophobic drug For macromole-cules

28. Patch technology for protein delivery: • Transdermal delivery of large proteins is a novel and exciting method because no commercial technology currently available incorporates proteins into transdermal patches. • The manufacturing method involves dispensing very small droplets of a concentrated protein solution on a transdermal liner in a predetermined pattern. • The liquid is dried, leaving a dry and thin layer of formulated protein on top of the liner. • The highly water-soluble proteins are dissolved by the interstitial fluid that is secreted from the skin through the RF microchannels, thus forming a highly concentrated protein solution in situ.

29. Patch technology for protein delivery:

30. Patch technology for protein delivery: • The diffusion of the dissolved molecules occurs through the RF microchannels into the viable tissues of the skin across a steep concentration gradient. • This process brings about a high delivery rate and a peak-blood profile of the drug resembling that of a subcutaneous injection. • This manufacturing method enables complete and flexible control of the drug load on the patch, control of patch size and shape, and high manufacturing yield with minimal protein losses. • In addition, this method fully retains the stability and biological activity of the protein drug.

31. Patch technology for hydroplilic drug & hydrophobic drug • Under this technique, pretreating the skin allows aquatic channels to form across the stratum corneum, which provides significant enhancement in the permeability of water-soluble compounds. • Drugs that exhibit insufficient solubility in water can still benefit from the technology. • By increasing solubility using various formulation approaches, such as drug-cyclodextrin complexes or dissolving the drug in a water-alcohol mixture, the drugs are also able to permeate the skin.

32. Patch technology for hydroplilic drug & hydrophobic drug • Table I shows the in vitro skin permeability of various drugs in a dynamic diffusion-cell model using full-thickness porcine skin. The results show enhanced transdermal delivery with the hydrophilic compounds—granisetron hydrogen chloride (HCl) and lidocaine HCl which is study by Galit Levin.

33. Patch technology for hydroplilic drug & hydrophobic drug • The results show enhanced transdermal delivery with the hydrophilic compounds—granisetron hydrogen chloride (HCl) and lidocaine HCl. Lidocaine HCl is more water-soluble than diclofenac sodium and had higher delivery rates. • The effect of the compound concentration on its delivery rate was shown with testosterone (2% versus 6% in aqueous solution) and lidocaine HCl (2% versus 5% in aqueous solution). • The delivery rate increased linearly with the concentration of the loaded compound.

34. Patch technology for Macromolecules • The delivery of these macromolecules through a full-thickness porcine skin that had been pretreated with the device. An increase in molecular size brought about a decrease in delivery rate. • The largest 70-kDa molecule was successfully delivered transdermally through the RF microchannels.

35. A convenient, painless, and less invasive alternative to injection, a common method for administering large proteins and peptides in low manufacturing cost. In contrast to oral delivery , this avoid first pass effect and offers the benefit of immediate cessation of drug administration in case of an adverse effect or overdose. In contrast to passive delivery , this allow for the delivery of water-soluble drugs So, Microchannel based Trans Delivery System by using Radio Frequency ( RF) is a Novel Approch for Drug delivery system Advantage over other conventional techniques In contrast to Iontophoresis , this is use for long time There is also no molecular size limitation, no molecular electrical charge requirement, and no specific formulation pH constraint. In contrast to micro needle , this is use for potent & less potent drug, the more extended release the delivery system

36. Acknowledgement • Writing this acknowledgement has provided me with the great opportunity to note the enormous help & guidance given by various persons whose work was note worthy & can’t be diminished from my mind & soul. • I would like to thank www.pharmainfo.net to give me opportunity of presenting power point presentation regarding my interested topic. • I would like to thank our principal Dr. Avani F. Amin & other faculty members who encourage me for this purpose. • I would also like to thank librarian of my institute for giving me permission to utilize our library resources. • Finally, I would like to mention a very special thank to my co-author who give me his valuable time, support and constant guidance with continuous suggestions to make this presentation very effective. • I would like to thank our principal Dr. Avani F. Amin who recommended Zydus Cadila for our industrial training.

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38. References • A.S. Sintov et al., "Radiofrequency-driven Skin Microchanneling as a New Way for Electrically Assisted Transdermal Delivery of Hydrophilic Drugs," J. Controlled Release, 89 (2), 311–320 (2003). • Z. Avrahami, "Transdermal Drug Delivery and Analyte Extraction," US Patent No. 6,148,232 (2000). • Z. Sohn and Z. Avrahami, "Monopolar and Bipolar Current Application for Transdermal Drug Delivery and Analyte Extraction," US Patent No. 6,611,706 (2001). • G. Levin et al., "Transdermal Delivery of Human Growth Hormone through RF-Microchannels," Pharm. Res. 22 (4), 550–555 (2005). • M.R. Prausnitz, S. Mitragotri, and L. Langer, "Current Status and Future Potential of Transdermal Drug Delivery," Nature Rev. Drug Disc.3 (2),115–124 (2004).

39. Thank you