The document discusses implantable microchip drug delivery systems. It provides an overview of controlled and pulsatile drug release mechanisms. Microfabrication techniques used to produce the microchips are also described, including the design of reservoirs, caps, and circuitry. Specific examples of drugs delivered by microchips are given. Challenges include limited drug amounts, required drug potency, and lack of degradability. However, microchips could reduce dosing and precisely control drug timing and levels.

1. SUBMITTED BY
MOHAMED ABUSALI VKS
DEPARTMENT OF PHARMACOLOGY

2. CONTENTS
1. INTRODUCTION
2. CONTROLLED RELEASE &PULSATILE
RELEASE OF DRUG
3. OVERVIW OF MICROFABRICATION
TECHNIQUE
4. DESIGN &COMPONENTS OF
IMPLANTABLE CONTROLLED RELEASE
MICROCHIP
5. CHALLENGES AND POTENTIAL
PROSPECTIVE OF MICROCHIP
6. BIOCOMPATABILITY
7. CONCLUSION
2

3. 1.INTRODUCTION
1. Now a days, synthesis or discovery of new chemical entities, with desirable therapeutic
properties but without undesirable side effects, was one of the major goals of
pharmaceutical research.
2. Pharmacokinetic and pharmacological studies have revealed that the rate and extent of
drug absorption rather than the dose, ultimately regulate therapeutic properties in
systemic treatment(review Urquhart et al., 1984).At present, controlled drug delivery
technology is one of the most rapidly advancing areas of science for human health care
(review Langer, 1990).
3. Many chronic medical conditions require taking specific drugs at specific dose levels on a
regular/periodic basis (review Polla et al., 2000) but patients often overlook, are
unwilling, or are unable to take their medication during long time using of medications
(review Santini et al., 1998; Kuo & Violante, 2012).
4. A variety of devices for controlled drug delivery have been developed in last few years.
Among them micropumps, osmotics pumps and micro electro mechanical systems
(MEMS) based drug delivery devices.
5. The use of traditional microfabrication techniques are the recent and alternative method
of creating drug delivery platforms and these are the same processing techniques for
manufacturing the microelectronic chips (review Breimer, 1999; Tao & Desai, 2003). 3

4. 2.CONTROLLED RELEASE AND PULSATILE RELEASE OF DRUG
4

5. 1. In general, injected or ingested drugs follow first-order kinetics, with initial high blood
levels of the drug after the first administration, followed by an exponential fall in blood
concentration which often can show toxicity and diminished efficacy respectively.
2. Sustained or pulsatile drug release is achieved by using controlled release of drug delivery
(review Hilt & Peppas, 2005) which means the rapid and transient release of a certain
amount of molecules within a short time-period immediately after a predetermined off-
release period (review Jain et al., 2011). This delivery method works better in certain cases
because it closely mimics the way in which the human body naturally produces some
compounds (review Santini et al., 2000a)Ex: insulin, anderior pituitary hormone,
gonadotrophin hormones.
ADVANTAGES OF CONTROLLED DRUG DELIVERY SYSTEM
(1) Maximization of efficacy–dose relationship.
(2) Reduced toxicity and intensity of side effects.
(3) Protection of mucosa from irritating drugs.
(4) Enhancement of patient compliance and convenience.
(5) Controlled administration of a therapeutic dose at a desirable rate of delivery.
ADVANTAGES OF MICROCHIP IN CDDS
1. Drug molecules are released from the reservoir in the predetermined manner.
2. Which can avoid the frequent administration of drugs to the patients.
3. Microchip have number of reservoir so different types of dosages are stored in invidual
reservoir.
4. Different types of dosage form can release at a same time.
5. Which either biodegradable or non biodegradable.
5

6. 3.MICROFABRICATION TECHNIQUE
1. Microscale devices inherently have many benefits over their conventional counterparts.
Advanced micro and nanotechnologies have enhanced the development of new drug
delivery technologies for the transformation of biological prospective into clinical
authenticity (review LaVan et al., 2002; Langer & Peppas, 2003). Till date, a miniature
device can be the prime element to the manufacture of portable, hand-held, or
implantable devices, which is highly desirable for drug delivery devices.
2. For microfabrication, the most important techniques are photolithography, soft
lithography, film deposition, etching and bonding (review Betancourt &
BrannonPeppas, 2006). These devices are fabricated by the repetitive application of unit
process steps such as thin-film deposition, photolithography and etching. Such
microfabrication techniques allow for the accurate control over surface
microarchitecture, topography and feature size (review Tao & Desai, 2003).
6

7. 4.DESIGN AND COMPONENTS OF MICROCHIP
•RESERVIOR OR SUBSTRATE
•RESERVIOR SEAL OR CAP
•DEVICE CIRCUITRY AND SOURCE OF POWER
7

8. SUBSTRATE
1. The etched or machined reservoirs containing substrates serve as the support for the
microchip (review Cima et al., 2000). Any substrate material, which can serve as a
support such as ceramics, semiconductors and degradable (e.g. polyethylene glycol) and
non-degradable polymers (e.g. silicon) (review Uhrich et al., 1999; Santini et al., 2005,
2011), polycrystalline and amorphous silicon, glass or plastic materials (review Voldman
et al., 1999; Armani & Liu, 2000).
2. microchips can contain multiple drugs in a variety of forms, including solid, liquid or gel
(review Orive et al., 2004; Santini et al., 2005). The drugs which to released can be a
single drug or multiple drugs.
RESERVIOR CAP
Reservoir caps control the time at which molecules are released from the reservoirs. The
reservoir caps serves as anode in active devices and consists of a thin film of conductive
material such as copper, gold (review Santini et al., 1998, 1999; Tao & Desai, 2003), silver,
zinc (review Santini et al., 2005), platinum or titanium (review Grayson et al., 2004a), and
some polymers (review Santini et al., 1998).
FABRICATION MICROCHIP RESERVIOR AND RESERVIOR CAP
1. To control the both of rate and time release of multiple chemical substances, fabrication
methods are applied for microchips and also allow for the release of a number of
molecules in a continuous or pulsatile method. 8

9. 2. The device is microfabricated by means of a sequential technique using silicon wafer
(review Lang, 1996; Santini et al., 1999) and microelectronic processing techniques
including ultraviolet photolithography (review Santini et al., 1998; Hilt & Peppas,
2005), chemical vapor deposition (review Daniel et al, 2009), electron beam
evaporation (review Santini et al., 1998) and reactive ion etching (review Santini et al.,
2000b; Hilt & Peppas, 2005), bonding (review Santini et al., 2011) using highly
biocompatible materials.
3. The molecules of release systems for delivery are inserted in to the reservoirs by
injection, inkjet printing or spin coating (review Santini et al., 1998; Tao & Desai,
2003).
4. Etching of the exposed cap material in this reservoir is stopped after the desired cap
thickness is obtained.
CONTROL CIRCUITRY AND POWER SOURCE
1. The control circuitry consists of a timer, a demultiplexer, a microprocessor and an input
source, e.g. memory source, single receiver or biosensor could be integrated in
implantable microchips. As a source of power, lithium-based or rechargeable
microbatteries can be used (review Satini et al., 2000c, 2005).
2. Electrodes can be maintained by two primary control methods within a specific range.
one is potentiostatic control where the potential is constant during reservoir activation
and another one is galvanostatic control where the current is constant during reservoir
activation.
9

10. ACTIVE MICROCHIP FABRICATION PROCESS
10

11. PASSIVE MICROCHIP FABRICATION PROCESS
11

12. Therapeutic and
prophylactic molecule
Examples References
Antibiotics Tetracycline,
Chlorotetracucline,
Bacitracin, Neomycin,
Gentamicin, Erythomycin,
and Penicillin
Review Santini et al.(2005)
Antibacterials Sulfonamides, Sulfadiazine,
Sulfacetamide,
Sulfamethizole and
Sulfisoxazole, Nitrofurazone
and Sodium propionate
Review Santini et al. (2005)
Antimicrobial drugs Triclosan, Chlorhexidine Review Santini et al. (2005)
Anti-allergics Sodium cromoglycate,
Antazoline, Methapyriline,
Chlorpheniramine
Review Santini et al. (2005)
EXAMPLES OF MICROCHIP DRUG DELIVERY SYSTEM
12

13. Anti-inflammatories Hydrocortisone,
Hydrocortisone acetate,
Fluorocinolone,
Medrysone ii. Non-steroidal
agents: Indomethacin,
Diclofenac, Ibuprofen
Review Santini et al.
(2005); Review Sharma et
al. (2006)
Hormones Vasopressin, Parathyroid
hormone
Review Liu et al. (2007);
Elman et al. (2009)
Mydriatics Atropine sulphate,
Cyclopentolate,
Homatropine, Scopolamine,
Tropicamide, Eucatropine,
and Hydroxyamphetamine
Review Santini et al. (2005);
Staples (2010)
Angiogenesis inhibitors Steroids, Angiostatin Review Santini et al. (2005)
Other drugs Prostaglandins,
Immunomodulatory agent,
Antioxidants, Ion channel
regulators, Cytotoxic agents,
Anesthetics, Erythropoietin,
Metabolites
Review Santini et al. (2005);
Review Sharma et al. (2006);
Staples (2010).
13

14. 6.BIOCOMPATIBILITY OF IMPLANTABLE MICROCHIP
1. MEMS devices have unique biocompatibility issues. The biocompatibility of a fabricate
drug delivery microreservoir device depends only on those materials in contact with
tissue (review Grayson et al., 2004 ,Graham-Rowe, 2012) such as, silicon (used as a
substrate and structural material), gold (used for electrodes) and silicon dioxide, silicon
nitride etc. (used as dielectrics) (review Shawgo et al., 2002; Chung et al., 2008).
2. The implantable microchip devices directly interact with the body so the
biocompatibility of silicon and other materials of fabrication have become much more
important (review Grayson et al., 2004).
3. Silicon is exposed to body fluids inside the wells which causes bio-incompatibility, but
can be silanated by a number of simple surface passivation processes. Therefore, the
surface modifications can be applied to increase biocompatibility and decrease
biofouling (review Erickson et al., 2008; Shawgo et al., 2002).
14

15. CHALLENGES AND POTENTIAL PROSPECTIVE OF
IMPLANTABLE MICROCHIP FOR DRUG DELIVERY.
CHALLENGES POTENTIAL
PROSPECTIVE
REFERENCES
Limited amount of drug can
be released from an reservoir
Potential to lower total dose
due to local administration,
better than standard injection
Review Vogelhuber et al.
(2001); Staples et al. (2006)
Drugs of high-potency are
required
Capable of precise timing
and control,this is required
for chronic administration
and reduce or avoid systemic
release
Review Santini et al. (2005);
Staples (2010)
Potential impact of tissue
capsule
Avoids need for injection:
better than parenteral
administration
Review Staples et al. (2006);
Staples (2010)
Requires surgery for
implantation and removal
Polymeric chips do not
require surgical removal as
electronic chips
Review Staples et al. (2006)
15

16. The lack of degradability in
a biological system
No impact on oral,
probably little impact on
products administered via
topical or pulmonary
routes.
The drugs are
automatically released at
required concentration
after detecting the level of
drug in the body
therapeutic range.
Review Vogelhuber et al.
(2001); Staples et al. (2006)
Review Santini et al.
(2000c)
16

17. AN ORALLY ADMINISTERED DRUG DELIVERY MICROCHIP USING
WIRELESS TRANSMISSION OF POWER AND DATA CAN BE ACTIVATED
AT A SPECIFIC TIME OR AT A SPECIFIC LOCATION IN THE
GASTROINTESTINAL TRACT (SHEPPARD ET AL., 2007).
17

18. AN IMPLANTABLE MICROCHIP FOR RELEASING PARATHYROID
HORMONE FRAGMENT (FARRA ET AL., 2012).
18

19. 7.CONCLUSION
There is no doubt that in near future implantable microchip will replace the conventional drug
delivery systems which are using in these days. As a promising approach, a lot of
improvement is required for these implantable microchip devices including biocompati-
bility, accurate size and shape, more patient compliance for administration and improved
rate of drug delivery in surrounding fluid. The challenges for the microchips in coming days
are the possibility of the scaling-up processes and the improvement of the present implantable
microchips as multifunctional microchips which will be able to perform the different types of
biological and therapeutic necessities in the intervening time.
19

20. 20
REFERENCES
1. Robert Farra, Norman F. Sheppard Jr., Laura McCabe, Robert M. Neer,James M. Anderson, John T.
Santini Jr., Michael J. Cima, Robert Langer, First-in-Human Testing of a Wirelessly Controlled Drug
Delivery Microchip,research article,published on 22 feb,2012.
2. Dennis L. Polla, Arthur G. Erdman, William P. Robbins, David T. Markus, Jorge Diaz-Diaz, Raed
Rizq, Yunwoo Nam, and Hui Tao Brickner, Microdevices In Medicine,Annu. Rev. Biomed. Eng. 2000.
02:551–76.
3. Mark Staples, Karen Daniel, Michael J. Cima, and Robert Langer, Application of Micro- and Nano-
Electromechanical Devices to Drug Delivery, Pharmaceutical Research, Vol. 23, No. 5, May 2006 ( #
2006),DOI: 10.1007/s11095-006-9906-4.
4. Sarah L. Tao,Tejal A. Desai, Microfabricated drug delivery systems: from particles to pores, 0169-
409X/ 02 /$ – see front matter Ó 2002 Elsevier Science B.V. All rights reserved, doi:10.1016/S0169-
409X(02)00227-2,Advanced Drug Delivery Reviews 55 (2003).
5. John Urquhart, John W. Fara, and Kay L. Willis,ALZA Research, Palo Alto,Califomia, RATE-
Controlled Delivery Systems In Drug And Hormone Research, Annu. Rev. Pharmacol. Toxicol.
1984.24:199-236. Downloaded from www.annualreviews.org Access provided by University of Texas
Southwestern Medical Center on 01/22/15. For personal use only.
6. John Urquhart, Palo Alto; FelixTheeuwes, Los Altos, both of Calif, Drug Deliyery Sysmm Comprising
A Reservoir Containing A Plurality Of Tiny Pills,United States Patent, Feb. 28, 1984.

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