Controlling in Modern Drug Delivery Systems

Irina Gotsiridze, Paata Kervalishvili, Tohid Talebifar



Abstract—Nowadays Nanomedicine & Specifically Targeted Drug Delivery has been developed. One of the important
factors in DDS is control. DDS promise us control. But controlling in DDS is a little different from macro-controlling.
In this article we try to get an overview about DDS and controlling on it. We start with Nanomedicine and in the
following we talk about control theory and try to merge these two fields.

Index Terms— Nanomedicine, Targeted Drug Delivery, Drug Delivery Systems, Control Theory, Drug Delivery
Carriers, Targeted Absorption.

I. INTRODUCTION
“There’s Plenty of Room at the bottom” this is the sentence that Richard Feynman, Physicist Scientist,
said on 1959 who led us to new field of science that now we know it as Nanotechnology. But the word
nanotechnology was first explained by Tokyo Science University Prof. Norio Tnaiguchi in 1974 paper. In 1980s
decade Eric Drexler studied this issue and wrote first book on Nanotechnology; Engines of Creation: the coming
era of nanotechnology.
Nanotechnology and Nano-science started with 2 key developments:
1-Start of cluster science: knowledge
2-Invention of Scanning Tunneling Microscopy (STM): Instrument
Cluster science is the Science of Study group of atoms (between 3 to 3*10 7).
Nano is 10-9 (Ten to the power of -9) m. Nanoparticles are particles between 1 to 100 nanometers in size.
Particles are classified according to diameter:

1. Ultrafine particles are the same as nanoparticles and between 1 and 100 nanometers in size
2. Coarse particles cover a range between 2,500 to 10,000 nanometer
3. Fine particles are sized between 100 to 2,500 nanometer.

Nanotechnology has many applications in new technologies.One of the famous fields of nanotechnology is
Nanomedicine. Nanomedicine consists of two words first is Nano that refers to Nano science and second is
Medicine that refers to Medical applications. So Nanomedicine is a field of science & technology that talk about
the applications of Nanotechnology in medicine. But why the nanomedicine is important? We know many
(traditional) ways to Deliver Drugs such as deliver through Gastrointestinal System, parenteral & etc. These ways
have advantages and Disadvantages and some of them are already use. In traditional drug delivery we have two
problems first is Dose of drug in our body if the dose of drug in our body is high we have Toxic side effects of
drug and if the dose of drug is low we have ineffective of drug and because of this doctor said us for example use
this pills each 8 hour if you use later than this time or sooner than this time we have ineffective and Toxic side
effects Respectively. We need to stay drug dose in a specific level. Second problem is when we need to deliver
drugs in specific part (organ) of body that need to be treated. As we see two aspects are very important to drug
delivery:
1) Spatial placement
2) Temporal delivery
Spatial placement related to targeting the drug to a specific organ or tissue. (Position of releasing). Temporal
delivery controlling the rate of drug delivery to the target tissue (Time rate or velocity of releasing). Imagine the
day you can say, “Drug, come here; drug, turn on; drug, turn off.”
So as we can see the differentiation between traditional drug delivery and modern drug delivery is “Control”. We
need to control the spatial placement and temporal delivery to have an effective drug delivery. In figure.1 you can
see the differentiation between traditional and modern drug delivery. We want too decrease the dose frequency and
this is need control. Nanomedicine promises us control.

Manuscript received October 4, 2015.



Irina Gotsiridze, Professor, Georgian Technical University(e-mail: [email protected])

Paata Kervalishvili Professor, Georgian Technical University(e-mail: [email protected])
Tohid Talebifar Msc. Student Georgian Technical University (e-mail: [email protected])
 Fig.1 Differentiation between traditional and modern drug delivery
When we Control a dynamic system (system that changes its state with time) it means that we want to interfere
on its behavior for getting to our desirable outcome. Control theory is a theory that deals with influencing the
behavior of dynamical systems. Control systems may be thought of as having four functions: measure, compare,
compute and correct.  These four functions are completed by five
elements: detector, transducer, transmitter, controller and final control element. The measuring function is
completed by the detector, transducer and transmitter. In practical applications these three elements are typically
contained in one unit. A standard example of a measuring unit is a  resistance thermometer.  The compare and
compute functions are completed within the controller, which may be implemented electronically by  proportional
control, a PI controller, PID controller, bistable, hysteretic control or programmable logic controller. The correct
function is completed with a final control element. The final control element changes an input or output in the
control system that affects the manipulated or controlled variable. These theory & element uses in Macro-systems
Regularly, but in Drug delivery systems that most of these systems are in range about Micro and nano scales, we
need to modulating control theory into the our desirable applications. First we need to recognize what is our
desirable goal in DDS; as we said we want to decrease dose frequency in our body by controlling drug releasing
time in our target position. We put the drugs inside carriers these carriers need to transport these drugs into the
target position & then controlled releasing. Second we need to recognize our controlling elements, in most DDS
our five controlling elements are the same. In DDS scale our controller our detector and final elements are one.
And this one is our carrier our materials. Third as we know in controlling theory mathematical models have
important role, we need to have a mathematical model for our Drug Delivery System (DDS). So if we want to
categorize our discussion Drug Delivery Systems can divide in to the two subjects: 1- Targeted Delivering 2-
Targeted Absorption. First we talk a little about Target delivering that is done by the Carriers and second we talk
about Targeted absorption in Targeted drug delivery.
There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based
drug carriers, nano-particle drug carriers, dendrimers, etc. An ideal drug delivery vehicle must be non-toxic,
biocompatible, non-immunogenic, biodegradable,  and must avoid recognition by the host's defense mechanisms.
Liposome: A liposome is a spherical vesicle (a vesicle is a bubble of liquid within a cell that stores or transports
substances within a cell.) having at least one Lipid bilayer. The word liposome derives from two Greek
words: lipo ("fat") and soma ("body"); it is so named because its composition is primarily of phospholipids (are a
type of fat that contain phosphorus. They are major parts of all cell membrane because they form Lipid bilayer.)
As we see liposome lipid bilayer contain of two head: Hydrophobic head and Hydrophilic head. Because of this
characteristic of liposome we can use liposome for both Hydrophilic drug and lipophile drug. We use liposome as
carrier for Doxorubicin and daunorubicin anti-cancer drug already.

Fig.3 Liposome

Micelles: Another type of drug delivery vehicle used is polymeric micelles. They are prepared from
certain amphiphilic  co-polymers consisting of both hydrophilic and hydrophobic monomer units. They can be used
to carry drugs that have poor solubility.

Fig 3. Polymeric micelles

Dendrimers: are also polymer-based delivery vehicles. They have a core that branches out in regular intervals
to form a small, spherical, and very dense nanocarrie
 Fig. 4. Dendrimeres

Biodegradable particles: Biodegradable particles have the ability to target diseased tissue as well as deliver their
payload as a controlled-release therapy.Biodegradable particles bearing ligands to P-selectin, endothelial selectin
(E-selectin) andICAM-1 have been found to adhere to inflamed endothelium. Therefore, the use of biodegradable
particles can also be used for cardiac tissue.
Artificial DNA nanostructures: The success of DNA nanotechnology in constructing artificially
designed nanostructures out of nucleic acids such as DNA, combined with the demonstration of systems for DNA
computing, has led to speculation that artificial nucleic acid nanodevices can be used to target drug delivery based
upon directly sensing its environment. These methods make use of DNA solely as a structural material and a
chemical, and do not make use of its biological role as the carrier of genetic information. Nucleic acid logic
circuits that could potentially be used as the core of a system that releases a drug only in response to a stimulus
such as a specific mRNA have been demonstrated. In addition, a DNA "box" with a controllable lid has been
synthesized using the DNA origami method. This structure could encapsulate a drug in its closed state, and open to
release it only in response to a desired stimulus.
After we transport & deliver our drug into the target position we need to releasing drug. We need controlled
releasing. But how we can order to our carrier to releases drug in the target position, well many ways recognize for
this goal for examples for drug carriers that made up Polymers our control variable is PH & Temperature (T), in
certain PH & T these polymers start to decomposing and releasing drugs, Or in the Magnetic particles, external
magnetic field can be a good way to control the carriers. As we see the materials and structure of our carrier has
important role in our controlled releasing. Good mathematical modeling can help us in this issue. Targeted drug
delivery can be used to treat many diseases, such as the cardiovascular diseases and diabetes. However, the most
important application of targeted drug delivery is to treat cancerous tumors. The American Heart Association rates
cardiovascular disease as the number one cause of death in the United States. Each year 1.5 million myocardial
infarctions (MI), also known as heart attacks, occur in the United States, with 500,000 leading to deaths. The costs
related to heart attacks exceed $60 billion per year. Therefore, there is a need to come up with an optimum
recovery system. The key to solving this problem lies in the effective use of pharmaceutical drugs that can be
targeted directly to the diseased tissue. This technique can help develop many more  regenerative techniques to
cure various diseases. The development of a number of regenerative strategies in recent years for  curing heart
disease represents a paradigm shift away from conventional approaches that aim to manage heart disease.
For many years we use drugs and send them to our body without any control of them. Nanomedicine or
Specifically Targeted Drug Delivery promise us controlling. There are two subjects in DDS: 1- Targeted
Delivering 2- Targeted Absorption. Many delivery carriers has been recognized and synthesized such as polymeric
micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc. After we
Magnetic field and etc.
transport & deliver our drug into the target position release drug. PH, Temperature,
are using for control releasing. Targeted drug delivery can be used to treat many diseases, such as
the cardiovascular diseases and diabetes. However, the most important application of
targeted drug delivery is to treat cancerous tumors.

REFERENCES
(Periodical style)
[1] S. Chen, B. Mulgrew, and P. M. Grant, “A clustering technique for digital communications channel equalization using radial basis function
networks,” IEEE Trans. on Neural Networks, vol. 4, pp. 570-578, July 1993.
[2] J. U. Duncombe, “Infrared navigation—Part I: An assessment of feasibility,” IEEE Trans. Electron Devices, vol. ED-11, pp. 34-39, Jan.
1959.
[3] C. Y. Lin, M. Wu, J. A. Bloom, I. J. Cox, and M. Miller, “Rotation, scale, and translation resilient public watermarking for images,” IEEE
Trans. Image Process., vol. 10, no. 5, pp. 767-782, May 2001.
(Book style)
[4] A. Cichocki and R. Unbehaven, Neural Networks for Optimization and Signal Processing, 1st ed. Chichester, U.K.: Wiley, 1993, ch. 2, pp.
45-47.
[5] W.-K. Chen, Linear Networks and Systems, Belmont, CA: Wadsworth, 1993, pp. 123-135.
[6] H. Poor, An Introduction to Signal Detection and Estimation; New York: Springer-Verlag, 1985, ch. 4.
(Book style with paper title and editor)
[7] R. A. Scholtz, “The Spread Spectrum Concept,” in Multiple Access, N. Abramson, Ed. Piscataway, NJ: IEEE Press, 1993, ch. 3, pp. 121-123.
[8] G. O. Young, “Synthetic structure of industrial plastics,” in Plastics, 2nd ed. vol. 3, J. Peters, Ed. New York: McGraw-Hill, 1964, pp. 15-64.
(Published Conference Proceedings style)
[9] M. B. Kasmani, “A Socio-linguistic Study of Vowel Harmony in Persian (Different Age Groups Use of Vowel Harmony Perspective,” Inter
national Proceedings of Economics Development and Research, ed. Chen Dan, pp. 359-366, vol. 26, Singapore: IACSIT Press, 2011.  
[10] W. D. Doyle, “Magnetization reversal in films with biaxial anisotropy,” in Proc. 1987 INTERMAG Conf., 1987, pp. 2.2-1-2.2-6.
(Presented Conference Paper style)
[11] G. W. Juette and L. E. Zeffanella, “Radio noise currents n short sections on bundle conductors,” presented at the IEEE Summer Power
Meeting, Dallas, TX, June 22-27, 1990.
(Thesis or Dissertation style)
[12] J. Williams, “Narrow-band analyzer,” Ph.D. dissertation, Dept. Elect. Eng., Harvard Univ., Cambridge, MA, 1993.
[13] N. Kawasaki, “Parametric study of thermal and chemical nonequilibrium nozzle flow,” M.S. thesis, Dept. Electron. Eng., Osaka Univ.,
Osaka, Japan, 1993.
(Patent style)
[14] J. P. Wilkinson, “Nonlinear resonant circuit devices,” U.S. Patent 3 624 12, July 16, 1990.
(Standards style)
[15] Letter Symbols for Quantities, ANSI Standard Y10.5-1968.
(Handbook style)
[16] Transmission Systems for Communications, 3rd ed., Western Electric Co., Winston-Salem, NC, 1985, pp. 44-60.
[17] Motorola Semiconductor Data Manual, Motorola Semiconductor Products Inc., Phoenix, AZ, 1989.
(Journal Online Sources style)
[18] R. J. Vidmar. (August 1992). On the use of atmospheric plasmas as electromagnetic reflectors. IEEE Trans. Plasma Sci. [Online]. 21(3). pp.
876-880. Available: http://www.halcyon.com/pub/journals/21ps03-vidmar