1. INTRODUCTION:

In the world of modern medicine, scientist could derive or synthesize several molecules which can be used as therapeutic agents (drugs) for various ailments. The recent pharmaceutical researches focus on improving the safety and efficacy of these medicinal agents with the help of newer advancements in science and technology. Advancements in areas including material science, herbal technologies, biotechnology, genetic engineering, electronics, instrumentation technology, communication technology etc. favor the design and development of novel drug delivery systems. Presently, polymer based controlled drug delivery systems have captured the market replacing the conventional formulations.

Recently it has been demonstrated by some pharmaceutical scientist and technologists that there are enormous opportunities lying hidden in improving the drug therapy by electronically automated means, taking the pharmaceuticals into a new era or electronic drug delivery.¹

2. Electroceuticals and Electronic Drug Delivery Systems (EDDS):

The word ‘Electroceuticals’ will no more remain as a newer terminology as the pharmaceutical giants like GlaxoSmithKline (GSK) started seeking opportunities in the development and marketing of electronic drug delivery devices. 2,3 There is an active global discussion about the application of electronics into the drug delivery devices, including oral delivery of therapeutic agents by the means of “electronic pills”.

The bioelectronics, a branch of electronics which has already spread in the area of electronic diagnostic devices and methods is now extending towards the development of sensor modulated electronically controlled drug delivery.⁴ As termed today, electroceuticals are electric impulse generating wearable or implantable micro machines that can relieve pain, sleep apnea, deep brain stimulation for motor disorders or any other associated diseased conditions by neurostimulation.^2,5,6 Sooner or later several other electronic drug delivery systems (EDDS) will be classified under electroceuticals making it a specialty area under bioelectronics as well as in the pharmaceutical sciences.

Iontophoretic drug delivery is extensively studied by various researcher and a few of which there are in the market can be considered as an early version of electroceuticals. The Phoresor™, Vyteris and E-trans are some examples for these earlier Iontophoretic devices. As per regulatory limits by USFDA the current that can be used in humans without losing the barrier properties of the skin permanently is 0.5mA cm^-2. Any device using an electric source should comply with this limitation in order to market them in the regulated countries.^7-9 Further development of these EDDS will force the regulatory bodies to frame standards in the aspects of safety and efficacy of these devices.

E-cigarettes are one of the most popular electronic nicotine delivery device, which is widely available in the market today. They serve as an alternate to the regular tobacco based cigarettes as a ‘smokeless way of smoking’. It also can serve as a tool in withdrawal therapies.^10-12

Cassandra L. Weaver et al. proposed an implantable on-demand local drug delivery system which can release the drug on application of varies cues. Polypyrrole nano sheets doped with graphene oxide were used for the delivery of dexamethasone, an anti-inflammatory agent. The drug loaded onto the polymer network were released on application of electric current corresponding to the voltage applied. Electrochemically triggered release of doxorubicin was also reported by Lijie He et al. Flexible electrodes were electrophoretically modified to create a conjugate of graphene oxide and doxorubicin. Pulses of positive potential applied could drive the drug release from these electrodes.^{13, 14}

Chi Hwan Lee et al. developed a completely bioderodable, electronically programmable implant from which the drug release was controlled wirelessly. The system was composed of heat actuated lipid membrane in which various drugs were embedded. This was co-located with a wireless system meant for Joule’s heating by induction. An external radio frequency amplifier was used to induce heat in the system there by controlling the drug release.¹⁵

Dieter Becker et al. developed an orally ingestible capsule like electronic drug delivery device, Intellicap® comprising a microcomputer, pH and temperature sensors, drug reservoir, stepper motor and piston pump for solution or suspension delivery. (Figure1) The system is traceable and controllable remotely through an external computer, after oral administration. The system was tested on human volunteers for the delivery of diltiazem and the pharmacokinetic data were comparable to a marketed sustained release formulation of Mylan. Thus the Intellicap® was found to be bioequivalent to the branded tablets. It is also recommended to use Intellicap® as a tool for early determination of colonic absorption of drugs in animals or humans, before formulating them into an extended release preparation. The device can be further modified as a GI sampling device so as to assess the release profile of pulsatile drug delivery systems. Evonik is marketing two versions of Intellicap® for various biopharmaceutical research applications.^16-21

Fig 1: Representation of Intellicap® indicating its various components²²

The researchers from Massachusetts Institute of Technology, USA has recently developed a gel like wound dressing film which is incorporated with temperature sensors, LED indicators, siliconized titanium wires, drug release channels and drug reservoir in it. The electronic chip was made up of Poly dimethylsiloxane (PDMS) which made it flexible and stretchable for biological use. Chips and LED arrays were chemically bonded to a hydrogel matrix prepared out of cross-linked polyacrylamide and polyethylene glycol. The major advantages of these ‘smart’ wound dressings lies in their stretchability, softness and wet nature which makes them highly biocompatible.²³ Polypyrrole, a known conductive polymer is used to prepare nanoparticles loaded with fluorescein and daunorubicin as drugs.

On application of varying voltages in a controlled manner the fluorescent marker as well as the chemotherapeutic agent were released from the nanoparticles.²⁴

Polypyrrole being a conductive polymer was further modified with grapheme-mesoporous silica nano hybrid reservoirs to form a multifunctional system. This could be used as an on-demand drug delivery device and additionally the electrochemical stimulation could treat peripheral nerve injuries. It could also effectively inhibit amyloid-beta aggregate formation and thus preventing the progression of Alzheimer’s disease.²⁵

A light triggered drug delivery has been demonstrated by using diamond nanowires doped with boron. Covalent modification was made by O-nitrobenzyl containing ligands, to which various enzymes like lysozyme and horseradish peroxidase were attached by amide bond formation. A suitable light source added to the device with batteries or an external light source with controlled radiation intensity and wavelength can bring about the drug release possible.^{26, 27}

ActiPatch®, developed by BioElectronics Corporation, USA is a drug free analgesic patch works with electromagnetic pulses that modulate the afferent nerves thus to mask the pain. The battery powered device produce 1000 pulses per second and can be applied to an area of 100 cm². The device was tested clinically and in the earlier months of 2017 US FDA grant clearance for its OTC sales in the market.^{28, 29}

Various polymer based controlled release systems are developed for the treatment of disease like Parkinson’s and epilepsy.³⁰ Apart from all these conventional systems, Donghee Son et al. developed a skin patch which monitor the muscle movements, collect and store the data and deliver the drug in a controlled manner through the skin. The stored data can be accessed externally for statistical analysis. The system had temperature and muscle movement nano sensors and drug release systems. The system was flexible enough to attach to the skin which can stretch if necessary.³¹

3. Pharmacoelectronics:

After the emergence and establishment of various pharmaceutical specialties like Pharmacoeconomics, Pharmacovigilance, pharmacoinformatics, pharmaco genomics the next emerging branch in the near future may be termed as pharmacoelectronics. Substantiating the thoughts of Mr. Joseph R. Carvalko, pharmaco electronics will be a new branch of electronics that deals with the electronic means of drug delivery, there by curing the patients in an easier way.¹

The new area will have to learn about various aspects of electronics and communication technology with reference to medical devices. The major electronic components of an EDDS that to be dealt in detail may be as discussed below.

3.1. The power source:

Power source being the basic requirement for the functioning of an electronic device is the major challenge lying in the development of EDDS. A miniature power source with long duration of power supply at sufficient voltage intensity is essential. Researchers from MIT develop an ingestible electronic device that can power up from the gastric acid. The power is harvested by zinc and copper electrodes in the system and could be used to operate temperature sensor and wireless communication system. The system was successfully tested in pigs. The next generation power harvesting for ingestible devices may follow such kind for technologies.³²

Piezoelectric actuators were employed in several micro injection systems to provide adequate power to the pumping or flow regulating components. Polyhydroxyl butyrate-co-hydroxyvalerate (PHBV) is a natural polymer which undergo electrical polarization on application of pressure. The similar kind of properties are exhibited by various biological molecules also like proteins, nucleic acids, polysaccharides etc.³³

Abubakar Abid et al. tested a midfield wireless power transfer from an external device outside the body to an ingested device at various locations of GI tract. Antenna operating at 1.2GHz in tissues were utilized and were characterized in pigs and power levels of 123 μW, 37.5 μW and 173 μW were achieved for stomach, esophagus and colon respectively.^{34, 35}

3.2. Sensors:

Various sensors are often employed electronic drug delivery devices in order to collect the ambient data so as to assist the functioning of the device. These include chemical sensors (like glucose sensor), pH sensors, temperature sensor, pressure sensor, pulse monitor etc. These are made up of materials which show adequate biocompatibility so that they can reside in the body for longer durations without causing any harm to the neighboring tissue. Arrays of pressure sensing membrane of 800 µm was presented for the use of endoscopes. The sensing was based on the silicone microchannels filled with salted glycerol as a conductive medium. Patterned copper layers could improve the sensitivity of the system. Silicon nitride pressure sensing films were also developed for various biomedical applications.^36-38 using cellulose derivatives, biocompatible optical strain sensor was developed. Cholesteric liquid crystals with hydroxyl propyl cellulose were used to respond to various stimuli like light, mechanical stress, temperature etc.³⁹ Hydrogel based piezoresistive sensor was developed which respond to different stimuli like glucose, pH and swelling.⁴⁰

3.3. Micro pumps and flow regulators:

Different types of pump and flow regulating units are employed in implantable, wearable as well as in ingestible EDDS in order to regulate and modify the rate of drug release. The drug reservoirs are mostly filled with drug solutions and are allowed to flow though specialized channels modulated by various pumps and valves. Q-Core Electronic Drug Delivery Systems by Q-Core Ltd. Present various multi therapy pumps for infusions as well as enteral therapies in both human beings and animals. An electromagnetic propulsion technology that control flow rates from 0.1-1000 ml/h, is claimed to improve the accuracy and continuity of flow of drug solutions.⁴¹ A valve less piezoelectric micropump was explained by Qifeng Cui et al. The pump consist of a pump membrane and inlet and outlet diffuser nozzles and were fabricated with silicone on a glass substrate. The analysis of the simulated micropump showed a linear pressure flow of the drug solution.⁴² High performance piezoelectric micropump with cantilever valves were designed and compared. The optimized cantilever valves produced satisfactory output rates for drug delivery. ⁴³

3.4. Microprocessors:

Microprocessor act as the major decision making and controlling unit in a electronic drug delivery system. Miniaturized processors with low power requirements are preferred for the use in implantable and ingestible devices. Microprocessor based device was constructed that used algorithms to identify cardiac arrhythmias which can detect various levels of tachycardia. The system was tested with large database from various cases of atrial flutter ranged from 149 to as high as 335 beat rates in a minute. Automatic drug infusion system was also developed for the control of arrhythmia.⁴⁴ A microprocessor based device developed for the recreation of gastro intestinal motility consisted four elements; a microcontroller (ATMEL AT90S2313), 4 channel digital-analog converter (MX7225), 4 channel analog amplifier (NJU201A) and 4 channel analog electronic switch (OPA445). Various parameters including the amplitude of the simulating voltage output were programmable.⁴⁵

3.5. Wireless communicator and antennas:

Several communications systems have been tested for data transfer and control of implanted and ingested devices. Realized systems were developed by animal testing and human cadaver testing followed by clinical studies in volunteers. Capacitive intrabody communication were tried with transmitter and receiver electrodes placed in the body. Galvanic coupling based wireless communication was successfully tested, which required only a small amount of power of 8 µW.^46-48

4. Electro pharmaceutics:

‘Electro pharmaceutics’ can be a specialized branch of pharmaceutics where the pharmacy graduates and pharmaceutical formulators learn about basic electronics, circuit designs, power sources and control devices, micro valves, microfluidics, microprocessors, Nano processors, their coding and programming and their application in drug delivery devices. Electronic drug delivery can offer a greater control in drug therapy over polymer based controlled drug release systems.

5. CONCLUSION:

From the above data it may be obvious that the drug therapy tomorrow may be following an electronic way, where a well-controlled drug delivery can be possible which can further be controlled by a physician from his office wirelessly. This may introduce specialized subject areas and chapters such as ‘Pharmacoelectronics’ and ‘electropharmaceutics’ into a formulators textbook.

6. End note:

Any EDDS device developed should assure the biocompatibility in materials used, design and construction. Failing in these aspects may cause serious injuries to the patients that can even be fatal.^49-54

7. CONFLICT OF INTEREST:

The Author(s) declare that there are conflict of interest in this manuscript.

8. REFERENCES:

1. Carvalko JR. PharmacoElectronics Emerge. IEEE technol society magazine 2015:36-40.

2. Famm K, Litt B, Tracey KJ, Boyden ES, Slaoui M. Drug discovery: A jump-start for electroceuticals. Nature 2013; 496:159-61.

3. Megtirrell. GSK's big bet: Tapping our body's electronics: @CNBC; 2015 [updated 2015-03-11]. Available from: http://www.cnbc.com/2015/03/11/glaxosmithklines-big-bet-on-electroceuticals.html.

4. Ho JS, Yeh AJ, Neofytou E et al. Wireless power transfer to deep-tissue microimplants. Proc Natl Acad Sci U S A 2014; 111:7974-9.

5. Prutchi D, editor. Electroceuticals; Replacing drugs by devices enabled through advanced VLSI technologies. Technical Papers of 2014 International Symposium on VLSI Design, Automation and Test 2014:28-30.

6. Neurostimulation - Wikipedia 2017. Available from: https://en.wikipedia.org/wiki/Neurostimulation.

7. Brown MB, Traynor MJ, Martin GP et al. Transdermal drug delivery systems: skin perturbation devices. Methods Mol Biol 2008;437:119-39.

8. Chang SL, Hofmann GA, Zhang L et al. The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones. J control release 2000; 66:127-33.

9. Badkar AV, Banga AK. Electrically enhanced transdermal delivery of a macromolecule. J Pharm Pharmacol 2002; 54:907-12.

10. Farsalinos KE, Polosa R. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review. Therapeutic Advances in Drug Safety 2014; 5:67-86.

11. Callahan-Lyon P. Electronic cigarettes: human health effects. Tob Control 2014; 23:36-40.

12. D G. E-cigarettes: The growing popularity of an unregulated drug delivery device 2013 [updated 2013-08-19; cited 2017]. Available from: https://sciencebasedmedicine.org/e-cigarettes-the-growing-popularity-of-an-unregulated-drug-delivery-device/.

13. Weaver CL, LaRosa JM, Luo X, et al. Electrically Controlled Drug Delivery from Graphene Oxide Nanocomposite Films. ACS Nano 2014;8:1834-43.

14. He L, Sarkar S, Barras A et al. Electrochemically stimulated drug release from flexible electrodes coated electrophoretically with doxorubicin loaded reduced graphene oxide. Chem Commun 2017;53:4022-5.

15. Lee CH, Kim H, Harburg DV et al. Biological lipid membranes for on-demand, wireless drug delivery from thin, bioresorbable electronic implants. NPG Asia Mater 2015;7:e227.

16. Becker D, Zhang J, Heimbach T et al. Novel Orally Swallowable IntelliCap(®) Device to Quantify Regional Drug Absorption in Human GI Tract Using Diltiazem as Model Drug. AAPS PharmSciTech 2014;15:1490-7.

17. Van der Schaar PJ, Dijksman F, Shimizu J et al. First in Human Study With a Novel Ingestible Electronic Drug Delivery and Monitoring Device: The Intellicap. Gastroenterology; 140:S-766.

18. IntelliCap® - Evonik Health Care - Your competitive advantage 2017 updated 2017; cited 2017 May 21]. Available from: http://healthcare.evonik.com/product/health-care/en/custom-solutions/oral-drug-delivery/intellicap/pages/default.aspx.

19. Smart Diagnostics | Medimetrics 2017 [cited 2017 May 15]. Available from: http://medimetrics.com/smart-diagnostics/.

20. Maurer JM, Schellekens RC, van Rieke HM et al. Gastrointestinal pH and Transit Time Profiling in Healthy Volunteers Using the IntelliCap System Confirms Ileo-Colonic Release of ColoPulse Tablets. Plos One 2015;10:e0129076.

21. Dijksman JF, De Jongh FT, Pardoel MG et al., inventors; Google Patents, assignee. Ingestible electronic capsule and in vivo drug delivery or diagnostic system 2014.

22. Medimetrics IntelliCap 2017. Available from: https://www.controlledreleasesociety.org/publications/imageresources/Pages/FI00009.aspx.

23. Lin S, Yuk H, Zhang T, et al. Stretchable Hydrogel Electronics and Devices. Adv Mater 2016;28:4497-505.

24. Ge J, Neofytou E, Cahill TJ, et al. Drug Release from Electric-Field-Responsive Nanoparticles. ACS Nano 2012;6:227-33.

25. Wu L, Wang J, Gao N, et al. Electrically pulsatile responsive drug delivery platform for treatment of Alzheimer’s disease. Nano Research 2015;8:2400-14.

26. Wang Q, Coffinier Y, Li M et al. Light-Triggered Release of Biomolecules from Diamond Nanowire Electrodes. Langmuir 2016;32:6515-23.

27. Peng Z, Ye R, Mann JA, Zakhidov D et al. Flexible Boron-Doped Laser-Induced Graphene Microsupercapacitors. ACS Nano 2015;9:5868-75.

28. Rawe IM, Kotak DC. A UK registry study of the effectiveness of a new over-the-counter chronic pain therapy. Pain Management 2015;5:413-23.

29. BioElectronics Corporation Announces US FDA OTC Clearances For Drug-free ActiPatch® Musculoskeletal Pain Therapy | ActiPatch® Pain Relief 2017 [cited 2017]. Available from: http://www.actipatch.com/bioelectronics-corporation-announces-us-fda-otc-clearances-for-drug-free-actipatch-musculoskeletal-pain-therapy/.

30. Narayanan A, George PA, DL. Application of 32 Factorial D-Optimal Design in Formulation of Porous Osmotic Pump Tablets of Ropinirole; An Anti-Parkinson's Agent. J Young Pharm. 2017;9:87-93.

31. Son D, Lee J, Qiao S, et al. Multifunctional wearable devices for diagnosis and therapy of movement disorders. Nat Nano 2014;9:397-404.

32. Nadeau P, El-Damak D, Glettig D et al. Prolonged energy harvesting for ingestible devices. Nature biomedical engineering 2017;1.

33. Stachowiak JC, von Muhlen MG, Li TH, Jalilian L et al. Piezoelectric control of needle-free transdermal drug delivery. J Control Release 2007;124:88-97.

34. Abid A, O’Brien JM, Bensel T et al. Wireless Power Transfer to Millimeter-Sized Gastrointestinal Electronics Validated in a Swine Model. Scientific Reports 2017;7:46745.

35. Wireless Power Can Drive Tiny Electronic Devices in GI Tract 2017 [updated 2017-04-28]. Available from: https://www.dddmag.com/news/2017/04/wireless-power-can-drive-tiny-electronic-devices-gi-tract.

36. Arabagi V, Felfoul O, Gosline AH et al. Biocompatible Pressure Sensing Skins for Minimally Invasive Surgical Instruments. IEEE Sensors Journal. 2016;16:1294-303.

37. Kvist PH, Jensen HE. Recent Advances in Continuous Glucose Monitoring: Biocompatibility of Glucose Sensors for Implantation in Subcutis. Journal Diabetes Sci Technol. 2007;1:746-52.

38. Medical Sensors for Implants and Catheters and NanoScale Systems GmbH: Disclaimer and Privacy InformationHow to find us Powered by Tempera and WordPress.; 2017. Available from: http://nanoss.de/medizintechnik/.

39. Kamita G, Frka-Petesic B, Allard A et al. Biocompatible and Sustainable Optical Strain Sensors for Large-Area Applications. Advanced Optical Materials 2016;4:1950-4.

40. Jorsch C, Schmidt U, Ulkoski D et al. Implantable biomedical sensor array with biocompatible hermetic encapsulation. J Sens Sens Syst 2016;5:229-35.

41. Q-Core Electronic Drug Delivery Systems 2017. Available from: https://www.medica-tradefair.com/cgi-bin/md_medica/lib/pub/tt.cgi/Q-Core_Electronic_Drug_Delivery_Systems.html?oid=22819〈=2&ticket=g_u_e_s_t.

42. Cui Q, Liu C, Zha XF. Study on a piezoelectric micropump for the controlled drug delivery system. Microfluidics and Nanofluidics 2007;3:377-90.

43. Junwu K, Zhigang Y, Taijiang P et al. Design and test of a high-performance piezoelectric micropump for drug delivery. Sensors and Actuators A: Physical 2005;121:156-61.

44. Fernald KW, Cook TA, Miller TK et al. A microprocessor-based implantable telemetry system. Computer 1991;24:23-30.

45. Lin Y, Turner LE, Mintchev MP, editors. Design of a portable microprocessor-based stimulator for the recreation of impaired gastrointestinal motility. ICECS 2001. 8th IEEE International Conference on Electronics, Circuits and Systems (Cat. No.01EX483);2001.

46. Dr. John McCreery CM, Dr. Cynthia Istook CM, Dr. Traci May-Plumlee CC et al. Interactive Electronic Textiles: Technologies, Applications, Opportunities, and Market Potential 2002:08-19.

47. Handa T, Shoji S, Ike S et al, editors. A very low-power consumption wireless ECG monitoring system using body as a signal transmission medium. Solid State Sensors and Actuators. Transducers '97 Chicago., 1997 International Conference on; 1997 16-19 Jun 1997.

48. Chandrashekar NS, Shobha Rani RH. Microprocessor in controlled transdermal drug delivery of anti-cancer drugs. J Mater Sci: Mater Med 2008;20:189.

49. Psathas KA, Kiourti A, Nikita KS, editors. Biocompatibility of implantable antennas: Design and performance considerations. The 8th European Conference on Antennas and Propagation (EuCAP 2014); 2014:6-11.

50. Baj-Rossi C, Cavallini A, Jost TR et al., editors. Biocompatible packagings for fully implantable multi-panel devices for remote monitoring of metabolism. 2015 IEEE Biomedical Circuits and Systems Conference (BioCAS); 2015:22-24 Oct.

51. Mertz L. Biocompatible Medical Devices: Raise the Bar for Health Care. IEEE Pulse 2013;4:16-20.

52. Spanier G, Eberhardt W, Ahrendt D et al., editors. Biocompatible assembling and packaging technology demonstrated by the integration of a micro sensor on a micro blood pump. Proceedings of IEEE Sensors (IEEE Cat. No.03CH37498); 2003; 22-24 Oct.

53. Verma L, Giri RN. An Algorithm for Enhancing Security of Medical Image. Research J Engineering and Tech 2010;1:50 – 52.

54. Pankaj R, Dhapake, Chauriya CB, Umredkar RC. Painless Insulin Drug Delivery Systems -A Review. Asian J Res Pharm Sci 2017;7: 01-07.

Received on 11.07.2017 Modified on 18.09.2017

Research J. Pharm. and Tech 2017; 10(10):3544-3548.

DOI: 10.5958/0974-360X.2017.00641.2